DEPARTMENT OF HEALTH AND HUMAN SERVICES

CENTERS FOR DISEASE CONTROL AND 

PREVENTION

Advisory Committee on Immunization Practices

June 27-28, 2007 

Atlanta, Georgia

Record of the Proceedings

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i

C O N T E N T S

Day 1, June 27, 2007 

WELCOME AND INTRODUCTION

 Dr. Abramson.......................................................................................... 1 

 Dr. Pickering........................................................................................... 1 

 Dr. Abramson.......................................................................................... 2 

HEPATITIS A VACCINE 

Introduction: Dr. Lieu............................................................................................... 3 

 Postexposure and Travel Prophylaxis: Dr. Novak.................................................... 4 

 Vote...........................................................................................................................10 

 Travel Recommendations: Dr. Novak...................................................................... 11 

 Vote.......................................................................................................................... 11 

VFC Vote: Dr. Calugar............................................................................................ 12 

VACCINE FINANCING

 Underinsured Children: Dr. Lee............................................................................... 13 

 AMA/AAP Immunization Congress: Dr. Orenstein................................................. 16 

 NVAC Financing Working Group: Dr. Birkhead..................................................... 18 

PROPOSED REVISIONS TO THE ADULT IMMUNIZATION SCHEDULE

 Introduction: Dr. Morse............................................................................................. 21 

 Information: Dr. Mootrey.......................................................................................... 21 

 Vote........................................................................................................................... 24 

PROPOSED REVISIONS TO THE CHILDHOOD/ADOLESCENT SCHEDULE

 Information: Dr. Calugar........................................................................................... 24 

CDC IMMUNIZATION SAFETY UPDATE

 Information: Dr. Broder............................................................................................. 27 

HERPES ZOSTER (SHINGLES) VACCINE

 Introduction: Dr. Treanor........................................................................................... 30 

 Information: Dr. Chaves............................................................................................ 30 

COMBINATION VACCINES

Activities and Next Steps: Ms. Stinchfield................................................................. 32 

MENINGOCOCCAL CONJUGATE VACCINE (MCV4)

 Introduction: Dr. Baker............................................................................................... 33 

 Epidemiology: Dr. Cohn............................................................................................. 33 

 Economic Model of Expansion: Dr. Ortega-Sanchez................................................. 34 

Vaccine Supply, Private Sector: Mr. Hosbach............................................................ 38 

 Vaccine Supply, Public Sector: Dr. Wallace............................................................... 39 

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Vaccine Safety: Dr. Iskander....................................................................................... 39 

New Recommendations: Dr. Cohn.............................................................................. 41 

 Vote...............................................................................................................................45 

ECONOMIC ANALYSES OF VACCINES

 Introduction: Dr. Lieu.................................................................................................. 45 

 Discussion: Dr. Mark Messonnier............................................................................... 45 

VACCINE SUPPLY AND IMPLEMENTATION

Information: Dr. Wallace............................................................................................. 47 

PNEUMOCOCCAL VACCINES

 Working Group Information: Dr. Morita..................................................................... 49 

VACCINES DURING PREGNANCY/BREAST-FEEDING

Introduction: Dr. Neuzil............................................................................................... 50 

 Information: Dr. Schrag............................................................................................... 50 

 Information: Dr. Skoff................................................................................................. 50 

Day 2, June 28, 2007 

INFLUENZA VACCINES

 Introduction and Update on LAIV: Dr. Fiore.............................................................. 53 

FluMist Safety Monitoring: Dr. Broder....................................................................... 57 

National Influenza Vaccine Summit: Dr. Mootrey...................................................... 60 

USE OF VACCINES IN PERSON WITH HIV/AIDS

 Children and Adolescents: Dr. Seward.........................................................................62 

 Vote.............................................................................................................................. 66 

 Adults: Dr. Mootrey..................................................................................................... 66 

UPDATE: ROTAVIRUS VACCINES 

 Introduction: Dr. Treanor............................................................................................. 67 

VAERS and VSD: Dr. Haber....................................................................................... 67 

Data Interpretation: Dr. Patel....................................................................................... 68 

RotaTeq and Kawasaki Disease: Dr. Izurieta.............................................................. 69 

UPDATE: HPV VACCINES

 Introduction: Dr. Gilsdorf............................................................................................ 72 

Safety Update: Dr. Iskander........................................................................................ 73 

Quadrivalent Safety Update: Dr. Dubin...................................................................... 74 

 Future Considerations: Dr. Markowitz....................................................................... 79 

UPDATE: VARICELLA

 Arkansas Outbreak: Ms. Lopez................................................................................... 82 

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AGENCY UPDATES............................................................................................................. 85 

PUBLIC COMMENT..............................................................................................................87

List of Participants and Attendees.....................................................................89 

List of Acronyms........................................................................................94 

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

CENTERS FOR DISEASE CONTROL AND PREVENTION

ADVISORY COMMITTEE ON IMMUNIZATION PRACTICES

June 27-28, 2007 

Atlanta, Georgia 

Minutes of the Meeting

The Department of Health and Human Services (HHS) and the Centers for Disease Control 

and Prevention (CDC), National Center for Immunization and Respiratory Diseases (NCIRD)

convened a meeting of the Advisory Committee on Immunization Practices (ACIP). The 

meeting was held on June 27-28, 2007 at CDC’s Global Communications Center in Atlanta, 

Georgia. The list of participants is appended to the minutes as Attachment 1. [Note: the list 

only includes persons who introduced themselves for the record, presented, made public 

comments, or registered prior to the meeting.]

Day One, June 27, 2007 

WELCOME AND INTRODUCTION

 Dr. Abramson welcomed attendees to the June 2007 ACIP meeting. Dr. Pickering 

introduced several international visitors, including Dr. Christine Ding-Ping Liu, Director of 

the Vaccine Center for the Centers of Disease Control in Taiwan, and members of the Turkish 

Adult Immunization Advisory Board. In addition, he welcomed the new liaison 

representative from Canada's National Advisory Committee on Immunization Practices, Dr. 

Joanne Langley from the Division of Infectious Diseases of the Department of Pediatrics, the 

Canadian Center for Vaccinology at Dalhousie University in Nova Scotia, and thanked Dr. 

Monika Naus, who was replaced by Dr. Langley. He noted several people who could not 

attend the meeting, including ACIP member Dr. Robin Womeodu. Dr. Geoff Evans was not 

present, but Dr. Indira Jevaji took his place; Dr. Norm Baylor was not present, but Dr. 

Florence Houn attended on his behalf; Dr. Wayne Hatchey from the Department of Defense 

was represented by Dr. Ted Cieslak; and neither Dr. Paul McKinney from the Association of 

Teachers of Preventive Medicine nor Dr. David Salisbury from the Department of Health in 

London were able to attend. Finally, Dr. Pickering announced that Dr. Sam Katz had been 

awarded a 2007 Pollin Prize for his contributions to pediatric infectious diseases and vaccine 

development, particularly his role in developing the measles vaccine with Nobel laureate Dr.

John Enders. 

Dr. Pickering noted that the CDC web site had been revised and that the ACIP site is 

updated frequently with the current version of the meeting agenda, meeting minutes and 

presentations, ACIP recommendations and other ACIP activities 

(http://www.cdc.gov/vaccines/recs/acip/default.htm ). 

 Dr. Pickering explained that the goal in appointing members to the ACIP is to achieve 

the greatest level of expertise while minimizing the potential for actual or perceived conflicts 

of interest. To summarize conflict-of-interest provisions applicable to the ACIP, as noted in 

the Policies and Procedure manual, members of the ACIP agree to forgo participation in 

certain activities related to vaccines during their tenure on this committee. For certain other 

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2

interests that potentially enhance a member's expertise while serving on the committee, CDC 

has issued limited conflict-of-interest waivers. Members who conduct clinical vaccine trials or 

serve on safety data monitoring boards may serve as consultants to present to the committee 

on matters related to those vaccines. However, they are prohibited from participating in the 

deliberations or votes of the committee on issues related to those specific vaccines. 

Regarding other vaccines of an affected company, a member may participate in discussions 

with the proviso that he or she abstains on all votes related to the vaccines of that company. 

ACIP members who may have a potential conflict of interest should make it known by 

disclosing all of their vaccine-related financial interests and work. 

 Dr. Abramson noted that the terms of four members, including himself, would expire 

on June 30th. He presented those members with a certificate of appreciation and thanked them 

for their many contributions to ACIP over the years. Dr. Ban Allos, Dr. Janet Gilsdorf, and 

Dr. John Treanor all spoke briefly about what working on the committee had meant to them. 

 Dr. Abramson added his appreciation of the incredible talent found among the ACIP 

committee members, the liaisons, and particularly the full-time CDC staff. He then pointed 

out some of the accomplishments he had witnessed, starting in 1999, when thimerosal was 

becoming an important topic and rotavirus vaccine was causing problems over the issue of 

intussusception. Influenza vaccine has gone to an age-based rather than a risk-based 

recommendation and appears to be moving toward a universal recommendation for all 

children, if not for adults. Progress has been made on the ACIP-HICPAC joint statement on 

immunization of healthcare workers, but that needs further emphasis. 

 In 1999 the committee voted to stop the use of rhesus rotavirus vaccine in the U.S., 

with the understanding that the risk-benefit ratio differed tremendously from that of 

developing countries. However, manufacturers developed other safer rotavirus vaccines, 

which will be introduced into developing countries in the next few years. 

The committee approved varicella zoster recommendations that now include the use of 

a routine second dose and will be looking at its impact on decreasing the occurrence of 

varicella disease and fixing the age shift in the occurrence of the disease. The recommended 

use of MMRV, despite occasional vaccine shortages, will help decrease the number of 

injections that children need. The herpes zoster vaccine is aimed specifically at older adults 

and is now recommended for routine use. 

 The development of an adolescent platform was a major move forward, especially use 

of a conjugated meningococcal vaccine. Tdap was recommended for use in adolescents as 

well as adults and healthcare providers. The pertussis component of this combination vaccine 

will have more impact now that it is being used in adolescents and adults. The impact of the 

human papillomavirus vaccine, the first vaccine specifically created as an anticancer vaccine, 

will be great; the issue of how to implement it remains to be solved. 

 The recommendation for use of hepatitis B vaccine in adults has been expanded, and 

perhaps should be expanded further. The hepatitis A recommendation also has been 

expanded to include all children 12 months of age and older, which has already shown a 

marked impact due to the high-risk part of the recommendation. The committee has 

continued to make recommendations based on good science and the best interest of the United 

States, without regard to cost. However, there is much to be done in the area of vaccine 

financing. 

Dr. Pickering thanked Dr. Abramson for all his work as chair of ACIP and as a 

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member of the influenza work group. He praised Dr. Abramson’s intellect and insight, as 

well as his compassion and integrity – particularly his concern for children and adults. 

 

Dr. Abramson asked committee members to state any conflicts of interest. 

 Dr. Allos: no conflicts. 

 Dr. Baker: no conflicts. 

 Mr. Beck: no conflicts. 

 Dr. Gilsdorf said she was an independent safety monitor on an NIH-sponsored vaccine 

trial for which she receives no compensation. 

 Dr. Hull: no conflicts. 

Dr. Lett: no conflicts. 

 Dr. Lieu: no conflicts. 

 Dr. Morita: no conflicts. 

 Dr. Neuzil: no conflicts. 

 Ms. Stinchfield: no conflicts. 

Dr. Treanor said he was doing clinical trials of influenza vaccines for Protein Sciences 

and for Merck, and had laboratory support for influenza work from GlaxoSmithKline. 

Dr. Morse: no conflicts. 

Dr. Abramson said he had no conflicts, but was on an NIH data safety monitoring 

board for the use of oseltamivir in children less than one year old. 

Dr. Pickering announced that there would be four new members joining the ACIP 

beginning July 1st and a fifth new member would be appointed in the very near future. The 

new members are Dr. Lance Chilton, a pediatrician with the Young Children's Health Center 

and Professor of Pediatrics at the University of New Mexico in Albuquerque; Dr. Paul 

Cieslak, Medical Director of the Oregon Immunization Program, Oregon State Public Health 

Division and Clinical Assistant Professor in Public Health and Preventive Medicine and 

Iinfectious Diseases at the Oregon Health and Science University; Dr. Allen Craig, State 

Epidemiologist from the Tennessee Department of Health, trained in family medicine; and Dr. 

Janet Englund, Associate Professor of the Division of Pediatric Infectious Diseases at 

Children's Hospital, the University of Washington and Fred Hutchinson Cancer Research 

Center in Seattle. As of July 1st, the new ACIP Chair will be Dr. Dale Morse, who has been 

an ACIP member since July of 2005. Dr. Morse is Director of the Office of Science and 

Public Health at the New York State Health Department. He will be assisted by Dr. Carol 

Baker, who will serve as the Vice Chair. Dr. Baker has been an ACIP member since July of 

2006 and is Professor of Pediatrics, Molecular Virology, and Microbiology at Baylor College 

of Medicine. 

HEPATITIS A VACCINE: POSTEXPOSURE AND TRAVEL PROPHYLAXIS 

Dr. Tracy Lieu, ACIP, WG Chair 

Dr. Ryan Novak, CDC/NCHHSTP/DVH 

Dr. Lieu began with a reminder that the ACIP had considered draft recommendations 

for postexposure prophylaxis for hepatitis A in February and at that time it was apparent that 

more clarification and discussion were needed. An ACIP hepatitis working group was formed 

and was able to reach consensus on the wording of the recommendations with the hepatitis 

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group within CDC. For postexposure prophylaxis for persons 12 months to 18 years old, 

vaccine is preferred to immune globulin (IG). For persons 19 to 40 years old, vaccine is 

preferred to IG. For persons over 40 years old, IG is preferred although vaccine can be used 

if IG cannot be obtained. Lastly, for patients with chronic liver disease, those who are 

immunocompromised, and children less than 12 months old, IG should be used. 

 These recommendations also affect the recommendations for hepatitis A travel 

vaccinations. Based on new data on vaccine effectiveness postexposure, the recommendation 

is that the first dose of vaccine at any time before travel should protect most healthy persons. 

Another recommendation is to add immune globulin for high-risk groups who are traveling in 

less than two weeks to areas of high transmission and to use IG for persons less than 12 

months old or who cannot receive vaccine. 

Dr. Novak summarized the conclusions from the February ACIP meeting when these 

data were first introduced, as well as the activities of the hepatitis work group. In February, 

Dr. John Victor presented the results of a clinical trial comparing efficacy of hepatitis A 

vaccine and immune globulin after exposure. This was followed by a discussion of these data 

and the policy implications of using hepatitis A vaccine alone postexposure. The work group 

reviewed the available data with respect to vaccine age groups and patients with chronic liver 

disease and other underlying medical conditions. It considered patient characteristics 

associated with more severe outcomes, response to vaccine, and the risk of transmission in 

common scenarios where postexposure prophylaxis is given in the U.S., and then drew on the 

experiences of those countries currently using hepatitis A vaccine post exposure. 

 Potential benefits of being able to use vaccine include long-term protection, ease of 

administration, acceptability, and availability. There is currently only one U.S. supplier of 

immune globulin, and the cost of IG has risen considerably over the last five to ten years, 

making it similar to that of hepatitis A vaccine. A single adult dose of IG is now about $20, 

and the pediatric vaccine dose under government contract is about $12. The adult dose is 

about $19. Another benefit of being able to use hepatitis A vaccine is that it brings U.S. 

practice in line with many other countries that recommend vaccine as postexposure 

prophylaxis. 

 In the randomized clinical non-inferiority hepatitis A vaccine postexposure trial 

conducted in Almaty, Kazakhstan, 4,524 households or day-care contacts aged 2 to 40 years 

were enrolled. Contacts had been exposed to index cases within two weeks after the index 

case symptom onset and had no history of hepatitis A or receipt of hepatitis A vaccine or IG 

within the last six months, chronic liver disease, or contraindications to vaccine or IG. There 

was a 1-to-1 randomization within households or day-care centers to receive vaccine or IG 

within two weeks after the index case symptom onset. The primary outcome was clinical 

hepatitis A among contacts that met the following three criteria: Positive for IgM anti-HAV, 

ALT level at least twice the upper limit of normal during an episode of illness with no other 

obvious cause, and symptoms consistent with viral hepatitis.

The results of that study indicated that the efficacy of hepatitis A vaccine was similar 

to that of IG, i.e., the noninferiority criterion was met. Because of the study design, the point 

estimate for vaccine efficacy required an assumption about IG efficacy. Assuming 90 percent 

IG efficacy, the point estimate of vaccine efficacy was 86 percent with a 95 percent 

confidence interval of the upper bound of the relative risk of 76 percent. If 85 percent IG 

efficacy was assumed, the point estimate of vaccine efficacy was 80 percent with the upper 

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bound of 64 percent. 

 Despite showing statistical noninferiority, the proportion of outcomes among vaccine 

recipients was slightly higher than among IG recipients, however the difference was small. 

Putting this in context, the risk of hepatitis A among vaccine recipients was never more than 

1.5 percent greater than among IG recipients. This study provided evidence consistent with 

many previous studies that IG might attenuate clinical illness when given after exposure.

 Looking at clinical endpoints by age, most cases were among children, so that was 

where the most inference was made, however the estimates for adults were similar. For the 

primary endpoint, 26 cases of laboratory-confirmed hepatitis A occurred among vaccine 

recipients and 18 occurred among IG recipients, yielding a relative risk among vaccine versus 

IG of 1.32. The one-sided 95 percent confidence interval upper bound of relative risk was 

2.3, which was well within the prespecified margin of 3.0. 

When stratified by age, the risk of hepatitis A was slightly higher among adults than in 

children in both the IG and vaccine groups. The point estimate of the relative risk for adults 

was very similar to that among children, but because of the relatively small number of adult 

participants, this stratified analysis has low power, so the confidence interval is wide. Similar 

findings were found when considering all suspected hepatitis A cases. 

After considering these results, the consensus of the work-group members was that 

there was sufficient evidence to support equivalency of vaccine and IG in both children and 

adults 40 years or younger. Because of the advantages of vaccine and equivalence to IG, the 

work group decided to state a preference for vaccine in this age group: “For healthy persons 

age greater than or equal to 12 months to 40 years, hepatitis A vaccine at the age appropriate 

dose is preferred to IG because of vaccine’s advantages, including long term protection and 

ease of administration.”

 At the time the Almaty study began, hepatitis A vaccine was not yet licensed down to 

12 months in the U.S., thus children aged 12 to 24 months were excluded from the study 

population. The work group decided to include 12- to 23-month-olds in the vaccine 

recommendations. There is no evidence to suggest persistence of maternal antibody past 12 

months, and the immunogenicity of the vaccine at 12 months is similar to that of 24 months. 

Currently, vaccine is licensed for use from 12 months in every country with a hepatitis A 

vaccine immunization program. Finally, current ACIP recommendations include this age 

group for pre-exposure vaccine use. 

 Unfortunately, results of the current study and previous information cannot answer all 

questions about how hepatitis A performs postexposure. First there is the question of age. 

Eligibility was restricted to age 40 and under in the Kazakhstan study. Most of the cases and 

study participants were fairly young, which is not surprising, given the epidemiology of 

hepatitis A in a country like Kazakhstan. All adults over age 40 are immune to hepatitis A, as 

are many young adults. No additional data are available to support preference for vaccine in 

these risk groups. 

 Considering the clinical characteristics of reported hepatitis A cases by age in 2005 

received through the National Notifiable Disease Surveillance System (NNDSS), the severity 

of hepatitis A disease increases with increasing age, as evidenced by the proportion of 

hospitalizations and deaths due to hepatitis A. Because of the absence of data about vaccine 

performance in persons older than 40 years and the risk of hepatitis A increasing with age, the 

work group made the following recommendation: “For persons greater than 40 years, IG is 

preferred because of the absence of information regarding vaccine performance and the more 

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severe manifestations of hepatitis A in this age group. Vaccine can be used if IG cannot be 

obtained.” 

 The next population addressed was persons who were diagnosed with chronic disease, 

immunocompromised, and people with other medical conditions. The Almaty study excluded 

patients who reported a diagnosis of chronic liver disease based on the concern about the 

increased severity of hepatitis A. It did not explicitly exclude people with other medical 

conditions, but in general the study population was young and healthy. Patients with chronic 

liver disease or other chronic medical conditions are known to have poorer response to 

vaccine pre-exposure. In addition, patients with chronic liver disease have a higher risk of 

more severe disease outcomes. 

 Dr. Novak then presented available data with respect to immune response to a single 

hepatitis A dose in selected populations. Among HIV-infected patients, the three relevant 

studies report a wide range of seroconversion after one dose of hepatitis A: from 10 percent to 

78 percent. Hepatitis A vaccination is recommended for patients with chronic liver disease, 

so there has been a fair amount of interest in studying the immunogenicity of the vaccine in 

these patients. In the three published studies of immunogenicity in these patients, the percent 

positive at four weeks ranges from 63 to 93 percent. It appears that the response rate is lowest 

in patients with decompensated cirrhosis. Finally, a few studies in liver and kidney transplant 

patients showed a much lower percent positive at four weeks. 

 A number of studies have indicated that the risk of severe outcomes from hepatitis A 

is higher among people with chronic liver disease (CLD). In a recent analysis of national 

death certificate data from 1999 to 2004 among 511 hepatitis A deaths, 229, or 45 percent, of 

deaths included a CLD-related ICD-10 code. The median age was 55 among CLD-related 

deaths and 69 among non-CLD-related deaths. Because of the suggestion of a suboptimal 

response to hepatitis A vaccine and the increased risk of severe hepatitis A outcomes in CLD 

patients, the work group decided to leave the current recommendation for IG in these groups: 

“IG should be used for children age less than 12 months, immunocompromised persons, 

persons who have been diagnosed with chronic liver disease, and persons for whom vaccine 

is contraindicated.”

 The work group also reviewed the risk of transmission of hepatitis A virus and the 

common scenarios in which postexposure prophylaxis is given in the U.S. The most common 

setting for IG use as a postexposure prophylaxis currently is among household and other close 

personal contacts. Outbreaks in childcare centers used to require IG, but now these outbreaks 

are rare. In these settings, secondary attack rates of 15 to 30 percent are common, with higher 

rates of transmission occurring from infected young children than from adolescents and 

adults. This is probably the setting in which the risk of transmission is highest. 

 Another common scenario is after exposure to an infected food handler. Based on 

surveillance data, 3 to 7 percent of reported hepatitis A cases are food handlers. About 5 

percent of food handlers worked while they were infectious and were felt to pose a 

transmission risk, i.e., people who might have been exposed to this food handler should be 

notified. However, the majority of food handlers do not transmit to patrons, as attack rates are 

generally low. In the context of these public notifications, an average of 350 IG doses per 

episode were administered. But there is a very broad range, and thousands of people received 

IG. The ability to use a vaccine might be quite beneficial in these circumstances. 

 Thus the working group recommended the following language: "Decisions to use 

vaccine or IG should take into account patient characteristics associated with more severe 

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manifestations of hepatitis A. Additionally, the magnitude of the risk of hepatitis A virus 

transmission from the exposure should be considered." 

 At the last meeting the committee heard about postexposure policies of Canada, the 

UK, and other European countries. The work group looked for new data, and reconsidered 

available data with respect to the experience in Canada and the UK. In Canada, vaccine 

without IG is the preferred method of postexposure prophylaxis, while IG continues to be 

used for infants and the immunocompromised. The work group reviewed one report of 

possible breakthrough infections, but it was found to be a transmission chain involving 

outbreaks in several child day-care settings. It also tried to get additional information about 

the rationale of the U.K. recommendations, which limit vaccine to exposures within the 

previous seven days and IG for exposures greater than seven days or involving people older 

than 50 years with cirrhosis or chronic HBV or HCV infections. But the data available to 

inform these recommendations were very limited. 

 In summary, vaccine offers a number of advantages over IG, and the flexibility to use 

vaccine in some circumstances would be beneficial. Available data suggest that vaccine is 

efficacious postexposure, but not all populations were studied. Pre-exposure immunogenicity 

data suggest that there are suboptimal responses to vaccine in persons with chronic liver 

disease and other chronic medical conditions. Any recommendation the committee might 

make about the ability to use vaccine would be an off-label use, as it is not approved through 

FDA for this indication. Additional data are not likely to be forthcoming, and additional 

studies would be logistically difficult. So the committee needs to balance the practical public 

health implementation considerations against the limitations of the available information. 

Among the materials provided to the committee was a copy of the current 

postexposure prophylaxis ACIP statement to provide background, as well as the new 

recommendations for postexposure prophylaxis. This document is meant to be a stand-alone 

MMWR ‘notice to readers’ with links to and from the current ACIP hepatitis A statement, 

thus it contains an introduction to the recommendation language to provide background 

information to the reader as to what changes were made and their rationale. These 

recommendations were clarified by appending the language from the current statement 

concerning common settings in which postexposure prophylaxis is given in the U.S. The only 

language change is the substitution of “IG or hepatitis A vaccine” for “IG.” In addition, the 

committee was provided with new travel recommendations for timing of pre-exposure vaccine 

dose. 

 The draft language for postexposure prophylaxis with hepatitis A vaccine is as 

follows: "Persons who recently have been exposed to hepatitis A virus and who previously 

have not received hepatitis A vaccine should be administered a single dose of vaccine or IG 

as soon as possible. Information about the relative efficacy of vaccine compared to IG 

postexposure is limited, and no data are available in persons aged greater than 40 years or 

those with underlying medical conditions. 

 "Therefore, decisions to use vaccine or IG should take into account patient 

characteristics associated with more severe manifestations of hepatitis A, including older age 

and chronic liver disease. Additionally, the magnitude of the risk of hepatitis A virus 

transmission from the exposure should be considered." 

 The next paragraphs deal with specific groups. "For healthy persons age greater than 

or equal to 12 months to 40 years, hepatitis A vaccine at the age appropriate dose is 

preferred to IG because of the vaccine's advantages, including long-term protection and ease 

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8

of administration. 

 "For persons greater than 40 years, IG is preferred because of the absence of 

information regarding vaccine performance and the more severe manifestations of hepatitis A 

in this age group. Vaccine can be used if IG cannot be obtained. 

 "IG should be used for children age less than 12 months, immunocompromised 

persons, persons who have been diagnosed with chronic liver disease, and persons for whom 

vaccine is contraindicated. 

 "Persons administered IG for whom hepatitis A vaccine is also recommended should 

receive a dose of vaccine simultaneously with IG. For persons who receive vaccine, the 

second dose should be administered according to the licensed schedule to complete the series. 

The efficacy of IG or vaccine when administered greater than two weeks after exposure has 

not been established." 

 

Discussion

 Dr. Allos asked whether adults over 40 who received IG as postexposure prophylaxis 

could also receive the vaccine and, if so, whether that should that be made part of the 

recommendation. 

 Dr. Neuzil was concerned about not having comparative randomized-controlled data 

on persons over 40. Looking at the hospitalization rates from the 15 to 39 group and the 40 to 

59, the real jump seemed to occur at 60 and over. Thus she wondered what data would be 

sufficient to recommend vaccine above the age of 40 or whether there were immunogenicity 

data in immunocompetent healthy people between 40 and 59 that could be used as a bridge. 

Dr. Novak replied that there were not enough data to inform that decision currently, nor are 

there any data in the pipeline. Dr. Neuzil added that if immunogenicity data would be helpful, 

those are relatively easy and inexpensive studies to do. 

Dr. Barbara Kuter reported that Merck did look at immunogenicity in individuals 

greater than 40, and in fact their dosage is different from individuals less than 40 because the 

response with the 25-unit dose was not as good. They moved to the 50-unit dose, for which 

there are data in individuals over 40, and seroconversion rates are comparable to those less 

than 40. 

Dr. Lett expressed concern about having so many age stratifications, which 

complicates the public health response when clinics have to rapidly vaccinate hundreds or 

thousands of people, particularly for restaurant exposures. The data about lack of transmission 

to patrons were interesting in that respect. Dr. Novak said those data were partly why the 

recommendations state a preference for IG , but that vaccine could be used if IG was not 

available. With situations such as restaurant exposures where the risk of transmission is 

believed to be low, vaccine could be used in older individuals. The worry is that older 

individuals with potentially underlying medical conditions that predispose them for more 

severe manifestations really need to receive IG. Dr. Abramson suggested that since serologic 

bridging data would not be published until October, that specific issue could be voted on 

October and put in the final document. 

 Dr. Hull asked whether only a single dose was being recommended postexposure. Dr. 

Novak clarified that a single dose was sufficient for postexposure prophylaxis but the second 

dose should be administered according to the licensed schedule to complete the series. Dr. 

Baker pointed out that exposed individuals who had had the vaccine series would not need 

postexposure prophylaxis. Dr. Abramson added that having had proven hepatitis A should 

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also preclude needing vaccine. 

 Dr. Treanor asked whether having been involved in an outbreak or other situations 

where prophylaxis was required, such as travel, would identify one as being at higher risk of 

subsequent exposures to hepatitis A than the general population. In other words, why would it 

matter whether they got the second dose? Dr. Treanor responded that it was just a question of 

logic.

 Dr. Schuchat noted that this country had already moved to a universal hepatitis A 

strategy, so the issue of high risk and low risk has changed because of the safety, 

effectiveness, and long-term protection of the vaccine.

Dr. Hull said he was confused by the statement indicating that the intensity of 

exposure should be considered in making the decision for IG versus vaccine. Dr. Novak 

replied that the recommendations needed to be seen in context. They include definitions for 

different settings where hepatitis A postexposure is often used in the U.S. and this provides 

some guidance as to the magnitude of risk. Household or close contact might be considered 

high risk versus the low risk of transmission in the case of an exposure to an infected food 

handler. Dr. Hull asked whether someone with high-risk exposure should get IG or vaccine. 

Dr. Novak explained that the magnitude of risk question pertains only to those individuals 

over 40 years of age, for which there are no efficacy data. For those people, one might use IG 

if there was a household or close-contact situation and vaccine if it was an exposure to an 

infected food handler, except where contraindicated. The recommendations are clear that 

persons at higher risk for more severe complications of hepatitis A should be receiving IG. 

Dr. Hull agreed with the context idea, but still felt the recommendation should be more 

explicit. 

 Dr. Morse asked whether one would be able to get data on safety and efficacy for 

people over age 40 from other countries. Dr. Abramson said he felt most people would feel 

comfortable with serologic data as a bridge. 

 Dr. Treanor pointed out that the statement actually says one should take into account 

the magnitude of the risk of transmission independently of the magnitude of the severity of 

disease and asked how that would be used to decide between the vaccine or IgG. Dr. Novak 

commented that the most common interactions with the state health departments were around 

helping decide the risk to those exposed. Dr. Bennett added that the decision was complex, 

but that it came down to whether or not to give prophylaxis and the statement needed to be 

simpler for the people giving the vaccine. 

 Dr. Bennett asked a related question about the timing of immune globulin and vaccine 

and whether immune globulin can be given after the vaccine if it is not available initially. Dr. 

Novak replied that that the work group had not specifically addressed this issue, but the 

important thing would be to get some kind of postexposure intervention put in place right 

away if it was a high-risk exposure. Dr. Hull pointed out that the language should clarify that 

this applies only to high-risk individuals. Dr. Pickering restated the previous question: If a 

person gets vaccine and then gets immune globulin, will the immune globulin inactivate the 

hepatitis A vaccine such that the whole series would have to be repeated? Dr. Bell responded 

that when vaccine and IG are administered simultaneously, the data indicate that the 

geometric mean concentrations from vaccine are somewhat lower. Other situations also 

suggest that when antibody is given, immunogenicity is reduced. Nonetheless, the antibody 

concentrations are still quite high, so there is no problem giving vaccine and IG at the same 

time. She speculated that there might be fewer problems giving IG after vaccine than giving 

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10

IG with vaccine.

An unidentified speaker commented that the stratification seemed rather complicated 

and suggested having one broad recommendation, with a guide for practitioners regarding the 

quality of evidence for one age group or another. 

 Dr. Bell said she appreciated the concern about bridging immunogenicity data, but felt 

the committee would need to be clear about what pre-exposure data would be relevant to the 

performance of vaccine postexposure. There are few data available with respect to preexposure immunogenicity in people older than 40. One could argue that the relevant 

information is response at two weeks after the first dose of vaccine, and that available 

evidence showing seroconversion at four weeks after a single dose of vaccine with differences 

in geometric mean concentrations in older versus younger adults might not be adequate 

bridging immunogenicity data to confidently recommend the equivalence of vaccine versus 

IG in people older than 40. She added a word of caution about whether bridging 

immunogenicity data in people over 40 would address the concern about the performance of 

vaccine in that age group. It is not as simple as stating that since there is 90 percent 

seroconversion at four weeks, vaccine works as well as IG postexposure. 

 Dr. Lieu asked whether the immunogenicity data presented for the older-than-40 age 

group in February were the same as that from Merck. Dr. Bell replied that the Merck data 

were not published, and that the data she presented used the previously licensed 

GlaxoSmithKline formulation, which is a three-dose series at half the dosage per shot, so they 

were not helpful for looking at the postexposure performance of a single dose at double. One 

published study explicitly looked at less than age 40 versus over 40 and at two weeks after the 

first dose; there was a difference in the percent positive between people less than 40 and older 

than 40, as well as a difference in the GMT. By four weeks, that difference closed up to about 

70 percent positive at two weeks after one dose of vaccine in people older than 40, as opposed 

to 90-plus percent positive. One could argue that this is relevant when considering using 

vaccine in a postexposure setting. Dr. Kuter confirmed that the amount of data at the twoweek time point was limited. The information at four weeks is much more substantial. 

 Dr. Abramson asked whether anyone still wanted to look at those data and to see if the 

recommendation as far as age cutoff should be changed. When there was no response, he felt 

the committee was ready to vote on the recommendation to preferentially vaccinate one-yearolds to 40-year-olds and to use IG in the other settings. 

Vote

 Dr. Morse made a motion in favor of the recommendation, which Dr. Baker seconded. 

Dr. Morse: yes.

 Dr. Treanor: abstain. 

 Ms. Stinchfield: yes. 

 Dr. Neuzil: yes. 

Dr. Morita: yes. 

 Dr. Lieu: yes. 

Dr. Lett: yes. 

 Dr. Hull: yes. 

 Dr. Gilsdorf: yes. 

 Mr. Beck: yes. 

Dr. Baker: yes. 

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11

 Dr. Allos: yes. 

 Dr. Abramson: yes. 

 

 Dr. Abramson reminded the committee members they would have a chance to look at 

this document before it was finalized and published and make comments about specific 

issues. Dr. Baker commented that, with respect to the over-40 group, it would be nice to get 

convincing data because that would make it easier operationally for everyone. 

Travel Recommendations

Dr. Novak presented the travel recommendations, which needed to be revised to bring 

them in line with the changes just voted on. The current ACIP travel recommendations for 

preexposure protection against hepatitis A state that travelers departing in more than four 

weeks should receive vaccine. If departure is within two to four weeks, then IG may be given 

for optimal protection. IG is recommended for children less than 12 months old, and persons 

allergic to or electing not to receive vaccine. 

 The work group found that the Almaty study findings and the new postexposure 

recommendations were relevant to preexposure vaccine use among at-risk travelers. The data 

regarding postexposure use suggest vaccine administered any time prior to departure should 

adequately protect most travelers, but may not be generalizable to all populations. 

The actual recommendation begins, "The first dose of hepatitis A vaccine should be 

administered as soon as travel is considered. Based on limited data showing equivalent 

postexposure efficacy of IG and vaccine among healthy persons aged less than or equal to 40 

years, one dose of single-antigen hepatitis A vaccine administered at any time before 

departure may provide adequate protection for most healthy individuals. 

 "However, no data are available for other populations or other vaccine formulations. 

For optimal protection, older adults, immunocompromised persons, and persons with chronic 

liver disease or other chronic medical conditions traveling to an area where risk of 

transmission is high less than two weeks after the initial dose, may also be administered IG, 

but at a different anatomic injection site. Completion of the vaccine series according to the 

licensed schedule is necessary for long-term protection." 

 There is no change in the rest of the recommendation, which reads as follows: 

"Travelers who elect not to receive vaccine or are less than 12 months of age or allergic to a 

vaccine component should receive a single dose of IG, which provides effective protection 

against hepatitis A for up to three months. Travelers whose travel period is greater than two 

months should be administered IG, and administration must be repeated if the travel period is 

greater than five months."

Discussion

 Dr. Mobeen Rathore noted that there was a time period of greater than four weeks for 

first line, then another one of two to four weeks. He thought just saying ‘less than four weeks’ 

would be easier for people in the field, unless there were specific differences between two and 

four weeks. 

 Mr. Beck asked about people who have liver disease or are immunocompromised, as 

covered in the previous recommendation. Dr. Novak said they should receive IG. 

Vote

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12

 Dr Abramson asked for a motion to accept the travel recommendations. Dr. Hull so 

moved and Dr. Gilsdorf seconded the motion. 

 Dr. Allos: yes. 

Dr. Baker: yes. 

 Mr. Beck: yes. 

 Dr. Gilsdorf: yes. 

 Dr. Hull: yes. 

Dr. Lett: yes. 

Dr. Lieu : yes. 

Dr. Morita: yes. 

 Dr. Neuzil: yes. 

 Ms. Stinchfield: yes. 

 Dr. Treanor: abstain. 

 Dr. Morse: yes. 

 Dr. Abramson: yes. 

VFC Vote 

Dr. Calugar reminded the committee that the vaccine-specific resolutions for the 

Vaccines for Children Program, or VFC, are revised any time there is a new or updated ACIP 

recommendation. For the just-approved postexposure use of hepatitis A vaccine, there were 

changes relating to eligible groups, but the recommended hepatitis A schedule and dosage 

intervals remained unchanged. A new section was incorporated in the VFC resolution, 

"Recommendation for use of hepatitis A vaccine for postexposure prophylaxis," which is 

similar to the just-approved ACIP recommendations. 

 The first paragraph includes general information about administering immune globulin 

and a statement about limited relative efficacy data when administrating hepatitis A vaccine 

compared to IG post exposure. The complex picture of a person's health condition, including 

age and chronic liver disease, as well as the magnitude of the risk of hepatitis A virus 

transmission, should be considered in this decision process. 

Specifics are needed for postexposure prophylaxis in selected special categories. 

Immune globulin should be used in healthy persons younger than 12 months of age, 

immunocompromised persons, persons who have been diagnosed with chronic liver disease, 

and persons for whom vaccine is contraindicated. For healthy persons aged 12 months 

through 18 years, hepatitis A vaccine at the age-appropriate dose is preferred to immune 

globulin because of the vaccine's advantages, including long-term protection and ease of 

administration. 

 The last paragraph emphasizes the importance of administrating hepatitis A vaccine 

simultaneously when IG is used for postexposure prophylaxis. For persons who receive 

vaccine, the second dose should be administered according to the licensed schedule to 

complete the series. The efficacy of IG or vaccine when administered later than two weeks 

after exposure has not been established. 

 Dr. Abramson asked for a motion to approve the VFC resolution. Ms. Stinchfield so 

moved and Dr. Baker seconded the motion. 

Dr. Lett: yes. 

 Dr. Hull: yes. 

 Dr. Gilsdorf: yes. 

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13

 Mr. Beck: yes. 

Dr. Baker: yes. 

 Dr. Allos: yes. 

 Dr. Abramson: yes. 

 Dr. Morse: yes. 

 Dr. Treanor: abstain. 

 Ms. Stinchfield: yes. 

 Dr. Neuzil: yes. 

Dr. Morita: yes. 

 Dr. Lieu: yes. 

 

Discussion

Dr. Amy Middleman from the Society of Adolescent Medicine asked if TWINRIX 

was recommended as one of the hepatitis A formulations that can be used postexposure on 

travel, even though there are no data. Dr. Bell clarified that the wording on TWINRIX for the 

travel recommendation was unchanged from the previous statement. The antigen content of 

hepatitis A in TWINRIX was only available for adults and it is half of that in the singleantigen vaccine. Since there is no information about the use of TWINRIX for postexposure 

prophylaxis, TWINRIX is not included in the hepatitis A vaccine postexposure prophylaxis 

recommendation. The VFC vote is the postexposure vote, not the travel vote, and so it has to 

do with hepatitis A vaccine, not TWINRIX. But TWINRIX currently is in the VFC language 

for preexposure prophylaxis for hepatitis A for 18-year-olds. 

VACCINE FINANCING

Dr. Grace Lee, Harvard Medical School, Boston Children’s Hospital

Dr. Walter Orenstein, Emory Vaccine Center

Dr. Guthrie Birkhead, New York State Department of Health, NVAC

Underinsured Children

Dr. Lee presented research looking at gaps in vaccine financing for underinsured 

children in the U.S. The number of vaccines routinely recommended for children and 

adolescents has more than doubled over the past decades; in 1985 there were vaccines to 

prevent seven diseases, whereas now there is protection against 16 infectious diseases. 

However, the cost has risen over 20-fold, from about $45 in 1985 to almost $1200 to fully 

vaccinate a female child in 2006. Many of the newer vaccines, such as HPV vaccine, 

rotavirus vaccine, meningococcal vaccine, and PCV7, are significantly more expensive. 

 In the U.S., financial coverage of childhood vaccines depends on whether or not a 

child has insurance and if so what type of insurance. Most private health insurance plans 

cover the cost of recommended vaccines, but some privately insured children are 

underinsured for vaccines. In those cases, patients either pay out-of-pocket or are referred to 

the public sector to receive publicly purchased vaccine from the state. Even that depends on 

whether a state has adequate 317 or state funding available. Publicly insured children (e.g., 

Medicaid) and the uninsured receive vaccines free of charge through Vaccines for Children 

(VFC). 

 The private sector accounts for 46 percent of vaccine purchase. Two federal funding 

sources, VFC and 317, account for 43 percent and 6 percent of the total vaccine purchase in 

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14

the U.S., respectively, and state funding contributes to about 5 percent. 

VFC is a federal entitlement program linked to ACIP, so when ACIP votes to include 

a vaccine the funding must be provided to purchase vaccine for eligible children, including 

the uninsured, Medicaid insured, American Indian or Alaskan natives, and the underinsured, 

but only if they are served at a federally qualified health center (FQHC) or a rural health 

center (RHC). Unfortunately, there are a limited number of these centers, so access is not 

readily available to all. In contrast, 317 funding is a discretionary annual appropriation that 

can be used for both children and adults. 

 As the number and cost of vaccines increases, VFC funding increases accordingly. In 

2007, nearly $2 billion will available for vaccine purchase from VFC funds. However, 317 

funding has remained level, which means additional funding for new vaccines is not available 

for those who depend on 317 funding, such as the underinsured. 

After the VFC program came into effect, there were three different types of state 

vaccine financing policies: universal, VFC enhanced, and VFC only. VFC-eligible children 

can receive vaccine in the public sector, in the private sector, or in FQHCs or RHCs. 

Underinsured children can receive vaccine in the public sector or the private sector. Fully 

insured children typically receive vaccine in the private sector. 

 In universal-purchase states, all vaccines recommended by ACIP are given to all 

children in all settings. In VFC-enhanced states, all vaccines are provided to VFC-eligible 

children and underinsured children in the public sector and the private sector, but not to 

insured children. In VFC-only states, all vaccines are provided to VFC-eligible children, but 

underinsured children in the public and private sectors do not necessarily have access to 

vaccines unless there happens to be adequate 317 or state funding available. 

 Historically, vaccinating underinsured children was not a problem because many of 

the vaccines were inexpensive and there was adequate 317 funding. The gap began to widen 

in 2000 when the pneumococcal conjugate vaccine was recommended for use. The addition 

of PCV7 actually doubled the cost of immunizing a child. Even though PCV7 was covered 

by VFC, many states could not cover it for other children, resulting in the creation of two new 

vaccine financing policies: universal select and VFC-enhanced select. The universal-select 

and VFC-enhanced-select states could provide some but not all vaccines to the underinsured, 

whereas they could provide all recommended vaccines to VFC-eligible children, including 

PCV7. 

 The objectives of the two-phase study presented by Dr. Lee were to describe the 

variation among states regarding access to new vaccines for underinsured children and to 

identify barriers to state implementation of new vaccines. In the first phase, one-hour 

qualitative telephone interviews were conducted with nine state immunization managers from 

November to December of 2005. States were chosen to include different types of vaccine 

financing policies. Phase 2 was a national survey; those not previously interviewed were sent 

written surveys and had one-hour semi-structured phone interviews. Surveys and interviews 

included questions about the status of the implementation of new vaccines, barriers 

encountered, and any changes in their vaccine financing policy. 

 The overall response rate was 89 percent; 48 of 50 state grantees participated in 

Phases 1 and 2 and two of six city grantees participated in Phase 2. The immunization 

program managers had been in their positions from six months to 27 years, with a median of 

five years. Fourteen percent of grantees were considered universal, 12 percent were universal 

select, 20 percent were VFC-enhanced, 16 percent VFC-enhanced select, and 38 percent were 

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15

VFC only. 

 There have been many changes regarding state vaccine financing policies since 2004. 

In general, states found that they needed to restrict their policies further, in part because of the 

number of new vaccines approved. Two states went from universal to universal select, five 

states went from VFC-enhanced to VFC-enhanced select, and three states went from VFCenhanced select to VFC only. Interestingly, one state temporarily went in the other direction 

because they were able to secure state funding to purchase of Prevnar for the underinsured. 

However, they expecte to go back to VFC-enhanced select as soon as new vaccines became 

available. 

 States and cities were asked whether they were able to provide vaccines to the 

underinsured in the private sector; 35 percent of underinsured children could not receive 

varicella vaccine in the private sector, 50 percent for Prevnar, nearly 70 percent for Menactra, 

50 percent for Tdap, and 56 percent for hepatitis A. Approximately half of underinsured 

children could not be vaccinated by their regular provider unless they could pay out of pocket. 

These underinsured children would typically be referred to the public sector. 

 When program managers were asked if they were able to provide vaccine for 

underinsured children in the public sector, nearly 40 percent of programs were unable to 

supply Menactra to those children. Nearly 15 percent were unable to supply Prevnar and 

hepatitis A, and 4 to 5 percent of the states were unable to supply Tdap or varicella. This is a 

significant concern because the public sector has been a safety net for these vulnerable 

children. Many public health practitioners voiced discomfort about turning away children 

who could not afford to pay for new vaccines. 

 Questions about barriers to implementation in the underinsured population were 

directed at states or cities that were not able to implement these vaccines for all underinsured 

children. Barriers cited included limitations on 317 funding and insufficient state funding, by 

which they meant they could not secure additional state funds for new vaccine purchase or, 

more commonly, their states had no money for any vaccine purchase. 

 Finally, program managers were asked about strategies used to address limitations in 

vaccine financing. Twenty-seven states had limited provider vaccine choice as a way to 

purchase the least expensive vaccine and be able to buy more vaccine. Twenty-five states 

received additional annual state appropriations to augment their budgets and thirteen states 

had expanded the designation of FQHCs or RHCs. Nine of 32 states with adult vaccination 

programs had to decrease the amount of adult vaccine purchased in order to assure enough 

money to purchase childhood vaccines. Four were fortunate enough to have had some healthplan appropriations and one state billed insurance companies for vaccines given to insured 

children in the public sector. 

 Those 13 states that expanded the designations of FQHCs or RHCs essentially 

increased the number of sites where underinsured children could receive VFC vaccine, which 

increased the number of underinsured children considered VFC eligible. Nine states have 

been able to designate some public VFC providers as FQHCs or RHCs. Three states have 

designated all public VFC providers so that underinsured kids could receive vaccine 

anywhere in the public sector and one state was able to designate all private and public VFC 

providers as FQHCs or RHCs, so underinsured children could receive all vaccines in either 

the public or the private sectors. 

 The study found that the current vaccine financing system was increasing the gap for 

underinsured children in the U.S. Given the estimate of about 14 percent of underinsured 

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16

children in the U.S., about 3.9 million children are unable to receive Menactra in the private 

sector and another 1.1 million underinsured children are unable to receive Menactra in the 

public sector. Limitations in 317 and state funding are clearly contributing to this gap. State 

immunization program managers are finding creative solutions to try to address limitations, 

but expanded access through funding and/or legislation is needed to protect this increasingly 

vulnerable population. 

 

Discussion 

 Dr. Hull asked what the birth cohort size was, to put the number of children unable to 

get Menactra in context. Dr Lee replied that there were usually 4 million children in a U.S. 

birth cohort. She added that there was an increasing number of high-deductible health plans 

or catastrophic health insurance plans, which do not necessarily cover the cost of preventive 

care, so this may increase the proportion of underinsured. 

Mr. Phil Hosbach of sanofi pasteur commented that the fact that 27 states had limited 

provider choice was not a new phenomenon; it has existed since the implementation of the 

VFC program. From this manufacturer's perspective, it is a public health policy that stifles 

competition and innovation. He added that it was useful to know the number of children not 

being covered for different vaccines by state, since they vary in size, scope and 

socioeconomic status. 

 Mr. Beck asked whether the gap could be expressed in terms of dollars. Dr. Lee 

replied that the calculation for Menactra would be $83 times the 1.1 million children who 

could not receive vaccine in the public sector. If one were to consider the 15 percent that were 

unable to receive Prevnar or hepatitis A, the total could easily reach $100 million. Dr. 

Schuchat added that CDC submitted a report to Congress about unmet needs in the 

underinsured and the cost of vaccine purchase had an estimated dollar figure for vaccines that 

were not reaching the underinsured. 

 Dr. Schaffner noted that HPV vaccine was not included in this estimate. Dr. Lee 

explained that HPV vaccine had just been introduced at the time of the study and many states 

had not yet implemented it. This will of course increase costs. Dr. Schaffner also pointed out 

that insurance that does not cover vaccines is not health insurance and that the study ended at 

the 19th birthday. Adult vaccination is also a concern. 

 Dr. Temte of the American Academy of Family Physicians commented that just 

because private insurers cover vaccine does not mean that private providers will be fully 

reimbursed for the cost of vaccine. For those involved in VFC, there are a lot of regulations 

around reimbursement and many private physicians are no longer willing to incur the costs. 

Dr. Abramson added that even human papillomavirus vaccine was being implemented in 

stages. The fact that VFC is an entitlement does not mean everybody has the money to 

implement the full recommendation. 

 Dr. Rodewald said that the Office of Management and Budget had provided sufficient 

funding to implement VFC for HPV. After 3 or 4 months of HPV implementation and 

availability of the contract, all of the state programs and all of the urban-area grantees had 

begun the HPV vaccine. Any limitations would relate to the degree to which a state wants to 

launch a catch-up campaign and variation in the amount going to adults. About a month ago, 

approximately 5 million doses of the vaccine had been sold and the VFC program had 

purchased about 60 percent of those doses. 

 

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17

AMA/AAP Immunization Congress

Dr. Orenstein shared information from an Immunization Congress sponsored by the 

American Academy of Pediatrics and the American Medical Association, which focused on 

concerns about the need to remove financial barriers to access, particularly for newly 

recommended vaccines. The first day was devoted to financing of vaccines recommended for 

children, within existing legislation as well as potential new legislation. Attendees included 

private providers, medical societies, public health societies, insurers, employers, 

manufacturers, and representatives from government at the federal, state, and local level. Nine 

recommendations were made, which have been under consideration by the National Vaccine 

Advisory Committee Vaccine Financing Working Group. 

 There was consensus on a number of points. Stakeholders supported universal access 

to all ACIP-recommended vaccines without financial barriers, although it was recognized that 

just removing financial barriers was not sufficient to ensure high immunization coverage. 

The private and public sector collaboration in vaccine delivery should be maintained. 

Through the VFC and other efforts, an army of private providers has been enlisted to decrease 

vaccine-preventable diseases by immunization. The medical home can add more medical 

benefits to children than vaccines alone, so vaccination of children by private providers ought 

to be supported. The best way to assure continued private-sector participation is to assure 

some reasonable return on that investment beyond costs. 

There was consensus that vaccines are different from most other preventive measures. 

Vaccinees receive direct protection, but because the vast majority of vaccine-preventable 

diseases are spread person-to-person, vaccination also indirectly protects other members of 

society. Solutions need to solve problems in every state, otherwise some states may become 

reservoirs for disseminating diseases to other states. Problems include under-insurance, 

inadequate or non-timely reimbursement, costs for vaccine ordering, storage, handling and 

paperwork, and the actual administration of vaccines. Unfairness of Medicaid reimbursement 

for administration was another big concern, with a range from $2 to more than $18. 

 The first working group recommendation was to work with federally qualified health 

centers and rural health clinics to delegate authority to public health clinics to serve 

underinsured children through the Vaccines For Children program. This decreases the 

pressure on the need for increased 317 appropriations and moves children from discretionary 

funds to entitlement funds. It also offers a safety net for referring underinsured children to 

public clinics for vaccines if other solutions to underinsurance are not found. All stakeholders 

represented at the meeting supported this effort, including manufacturers, provided it did not 

decrease the private sector market. Recent data from the Association of State and Territorial 

Health Officials indicate that 22 of the 64 immunization grantees have now implemented this 

delegation authority, including sixteen states, four urban areas, and two territories. 

The second recommendation was to obtain as soon as possible the actual cost of 

delivering vaccines in private practice settings, using gold-standard methods so that all 

stakeholders, including CMS, business groups and insurers, could accept the information as 

valid. Input from these stakeholders should be obtained prior to initiating the study and the 

AAP and AAFP could use that data to educate insurers and advocate for better reimbursement 

rates. Providers indicated that their number-one concern was inadequate administration fees, 

not vaccine fees. They also felt that the medical societies should advocate with insurers to 

have contracts that covered changes in mid contract, such as vaccine price increases or new 

vaccines added to the schedule. 

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A third recommendation was that the medical societies should work with 

manufacturers and distributors to obtain more favorable terms for payments for vaccine 

inventories. This is a major cash outlay, especially for smaller practices and for new 

vaccines. Solving this issue should be in the interest of the manufacturers and, if necessary, 

could be built into pricing. 

A fourth recommendation was that medical societies work with the AMA to better 

define all of the components that go into CPT codes for vaccine and vaccine administration. 

A fifth recommendation was that the National Vaccine Advisory Committee Vaccine 

Financing Working Group examine the potential role of tax credits for insurers and/or 

employers in eliminating underinsurance. The group felt there were not yet enough details to 

endorse such a recommendation, but it could be a positive incentive. 

 A sixth recommendation was to convene a working group of key stakeholders, 

including manufacturers, to determine whether some form of universal federal vaccine 

purchase or funding should be pursued. This option has been vigorously opposed by the 

vaccine industry in the past, but it might be designed in such a way as to gain their support. 

 The seventh recommendation was that the societies should obtain data from the 

Centers for Medicare and Medicaid Services that led to the current influenza administration 

fee and use that data to advocate at the state level for enhanced Medicaid reimbursement. 

There has not been sufficient publicity given to the tremendous variation in Medicaid 

reimbursement rates for administration, and the data from Recommendation 2 should be used 

to advocate for higher rates. 

 Recommendation 8 dealt with the cost of obtaining and administering combination 

vaccines, compared to individual vaccines. If they are shown to be more costly, there should 

be better reimbursement for combination vaccines. 

The last recommendation was that the American Academy of Pediatrics and the 

American Academy of Family Physicians should collect data on best business practices to 

minimize vaccine and vaccination costs and disseminate them to their members.

NVAC Financing Working Group 

Dr. Birkhead presented an update from the National Vaccine Advisory Committee 

Vaccine Financing Working Group. New vaccines added to the schedule and new 

recommendations have created a crisis in the delivery system. However, the problem is not 

readily visible because there has been no resurgence of vaccine-preventable diseases due to 

failure to vaccinate and morbidity from the diseases prevented by the new vaccines may not 

yet be recognized as a problem. 

 NVAC has a long history of looking at vaccine finance issues. In 2006-2007, a 

working group was charged with obtaining information from stakeholders on the challenges 

in creating optimal approaches to vaccine financing in both the public and private sectors and 

their impact on access; establishing a process for selecting and addressing two to three topics 

per year; developing specific targeted policy options in these areas; and presenting the 

findings and policy options to the full NVAC for discussion. Members of the working group 

included a number of NVAC members, as well as representatives from insurance, 

pharmaceuticals and academia. 

 The primary focus in the first year was childhood immunization. In the public sector, 

although vaccine is available through the Vaccines For Children program, administration fees 

are a problem. The Medicaid administration fee is very inadequate and the base rate has not 

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19

been updated since 1994. Uninsured children are eligible for VFC vaccine, but there is no 

mechanism to supply an administration fee. However, providers who participate in VFC 

cannot turn anyone away for inability to pay. The 317 program has not kept pace with the new 

vaccines that have come along. 

 In the private sector, providers are stressed in terms of the cost of maintaining an 

inventory. It becomes a cash-flow problem, along with loss of vaccines due to power failure 

or other reasons. There are concerns on the insurance side about the adequacy of 

reimbursement for vaccine costs and/or administration costs. 

 The working group obtained input from the various other NVAC subcommittees and 

stakeholders and commissioned a number of surveys to obtain data on the actual impact at the 

practice level. There are also other studies of cost of vaccination in process. Members of the 

working group attended the AMA-AAP vaccine financing congress. CMS is represented on 

the working group, and has helped the group understand the current system of Medicaid and 

Medicare reimbursement for vaccination. Individual vaccine manufacturers will be 

interviewed to gain their perspective, and something similar is planned for insurers. 

 Dr. Birkhead reported on two studies commissioned by the working group. The first 

was an assessment of charges and reimbursement for vaccines and administration fees in 

private practices. The purpose was to determine the range of prices paid for childhood and 

adolescent vaccines, the administration fees charged, and the reimbursement paid by three 

large insurers. Thirty practice managers were surveyed by telephone, from five non-universal 

purchase states, medium, small, and large, with metropolitan and non-metropolitan areas. 

Results are expected in the fall. 

 The second study looked at private provider attitudes regarding vaccine financing and 

to what extent they influence their willingness to adopt new vaccines. This is a crosssectional survey through the mail of a random sample from the AMA master file. Results are 

anticipated by the fall as well. 

 Meanwhile, work has begun on a draft of a white paper laying out the issues and 

making some recommendations. There is overall agreement on the goal: to ensure universal 

access to all vaccines recommended by ACIP for children and adolescents without financial 

barriers, and there are a number of conclusions. One is that the current public and private 

sector mixed-financing system for purchase of pediatric and adolescent vaccines has the 

capacity to deliver the currently recommended vaccines but it may not assure access to all 

children and adolescents without financial barriers. Financial incentives can play a major role 

in strengthening the system to deliver current as well as future recommended vaccines. 

 There appear to be wide variations in vaccine costs and reimbursements to providers. 

It is not clear that CPT codes take into account such factors as the need to enter data in the 

vaccine registries, time for parental counseling and discussion, maintaining reminder systems, 

and insurance policies against catastrophic loss of vaccine. 

 The group felt that HRSA and CDC should encourage federally qualified health 

centers and rural health clinics to work with their local public health departments to serve 

underinsured kids who cannot be served at the federally qualified health centers because of 

lack of access or availability. The Association of State and Territorial Health Officials is 

already working with states around this point. 

The maximum allowable reimbursement rates for administration in the Medicaid 

program should be re-examined. Once those rates are set, states need to contribute maximally 

to the vaccine administration fee and then draw down federal dollars to create the full 

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20

administration fee. CDC should collect data on actual non-vaccine costs of vaccinating in 

private practices, using a method that is accepted by the major stakeholders and passes muster 

with CMS and insurers, so that it can potentially form the basis of the new administration fee 

amounts. 

Medical and other relevant societies should work with the AMA to be sure that the 

CPT codes used for billing contain all necessary elements. Medical societies should collect 

data on best-business practices to help practices design their work load. 

 Vaccines may be recommended by ACIP in the middle of an insurance policy cycle, 

and so provider and insurance contracts should allow for increases in new vaccines or 

increases in existing vaccines mid contract. Vaccine manufacturers and third-party 

distributors should work with providers to reduce financial liability for initial inventories of 

new vaccine. There should be a mechanism to increase Section 317 funding when new 

vaccines become available and mechanisms to utilize the 317 funding to support 

administration fees. 

 NVPO should convene key stakeholders, including manufacturers and insurers, to talk 

about these issues in light of data from the surveys and other studies. The idea is to look 

outside the box and find solutions that would be mutually agreeable to all parties. For 

example, is there a way to design a federal vaccine universal purchase that has not been 

thought about yet, perhaps around a voucher system? 

 Regarding next steps, the practice and cost survey along with the draft white paper 

will be submitted to NVAC for consideration and potential adoption. Discussions will 

continue around the administration fees and Medicaid, to either increase those or improve 

state participation. Another option is to look at the Medicare influenza administration rate and 

see if that can be adopted in the Medicaid setting. Vaccine economic evaluation projects are 

encouraged. Finally, there will be a stakeholders meeting in the winter or early next year. 

Discussion 

 Dr. Lett asked whether anyone had thought about how to identify and address the 

ERISA problem. Dr. Birkhead replied that it had come up in the beginning. Self-Insured 

plans or ERISA plans are not regulated through state insurance departments, so it is more of a 

third-rail issue. Dr. Orenstein added that there has been legislation in the past that offered to 

open up ERISA, but it never went anywhere. It would be important to know how big the 

underinsured problem actually is. Old IOM estimates ranged from about 5 percent of the 

birth cohort up to about 13 or 14 percent. More recent data indicate about 7 percent. 

Dr. Rodewald commented that vaccines and vaccine coverage constitute a relatively 

small proportion of the total healthcare cost, so point estimates are difficult to obtain. They 

are not included in most surveys of insurance coverage. However, the point estimates from 

the IOM seemed to hover somewhere around 10 to 11 percent. The National Immunization 

Survey has added an insurance module that will include adolescents and help obtain 

underinsurance information. The 2001-2002 module was in the 10 to 11 percent range as 

well. 

Dr. Freed, as chair of NVAC, emphasized that this was all only draft language, which 

has not been approved by the working group. Once the full NVAC receives the 

recommendations from the working group, there will be a process of deliberation, which 

includes comments from federal agencies, the public, and the members themselves. NVAC 

has no statutory authority to enforce its recommendations; its role is to make specific

This document has been archived for historical purposes. (7/1/2007)
21

recommendations to the Assistant Secretary for Health and stimulate public debate. Then 

people can use those recommendations in their own way. 

Dr. Abramson asked if there was any sense about what the Undersecretary of Health 

might do. Dr. Gellin replied that the Assistant Secretary for Health was following the 

progress of this working group and got regular reports, so the good news was that people are 

listening to the debate. 

PROPOSED REVISIONS TO THE ADULT IMMUNIZATION SCHEDULE

Dale Morse, ACIP WG Chair

Gina Mootrey, CDC/NCIRD, ISD

 

Dr. Morse explained that the work group’s initial task was to add zoster to the adult 

schedule, but then members asked how they could actually promote and increase 

immunizations in this population and make the adult schedule more user friendly and 

consistent with the childhood and adolescent schedule. Potential future activities include 

revising healthcare worker recommendations and having focus groups review the Medical and 

Other Indications schedule. The hope is to publish this recommended adult immunization 

schedule in October 2007, which would correspond with a number of activities to promote 

adult vaccines, then incorporate the adult immunization recommendations into the next 

general recommendations for simplification, and eventually look at the adult immunization 

schedule for HIV-infected persons. 

Dr. Mootrey went over the changes made to the schedules and the footnotes. The 

proposed age-based schedule for 2007 and 2008 was presented. The bar for HPV vaccine has 

been shortened to show that it only goes through age 26. The bar for varicella vaccine is now 

yellow throughout. The previous one had yellow for 19 to 49 years and purple for 50 to 64 

years, pending zoster recommendations. The zoster vaccine bar is yellow for those 60 years 

and older. The yellow bar wording has been changed from “age requirements and lack of 

evidence of immunity” to an "and/or," so that this schedule would apply if one had age 

requirements and/or lack of evidence of immunity. Wording has been added giving a 

reference to the ACIP recommendations and the extent of available data. The URLs for the 

ACIP recommendations were updated and a note was added that meningococcal vaccine is 

covered by the injury compensation program. 

 Dr. Mootrey then presented the proposed revisions to the Medical and Other 

Indications schedule 2007 and 2008. The working group is proposing a revision to the title of 

this table, to indicate that the vaccines mentioned do not all have a specific recommendation, 

but that there is no contraindication and they may be given for these different groups. Mention 

is made that meningococcal vaccine is covered by the Vaccine Injury Compensation Program. 

The column for the immunocompromising conditions has been shortened and a footnote 

added because of the increasing number of conditions. To make things simpler, the 

immunocompromising conditions column is now adjacent to the HIV column. Because of 

indications for several of the vaccines, specifically varicella and MMR, the HIV column was 

split, based on CD4 count. 

 The chronic liver disease column used to have recipients of clotting factor 

concentrates as a risk group. Since that now only applies to hepatitis A vaccine, it has been 

taken out of the column heading but remains in the footnote for hepatitis A vaccine. 

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22

 For influenza vaccine, there is now a specific indication that TIV or LAIV can be 

given to healthcare workers, and there is now a yellow bar as opposed to a purple bar for the 

asplenia column. For meningococcal vaccine, the table indicates that one or more doses could 

be given, depending on various risk indications. 

 Zoster vaccine was added, with a contraindication for pregnancy, immunocompromising conditions, and HIV CD4 count less than 200. However, Dr. Mootrey said she 

had just attended a meeting of the DHHS-IDSA work group on revising the guidelines for 

prevention and treatment of opportunistic infections in HIV-infected persons, where it was 

felt that it would not be appropriate to indicate any kind of recommendation for zoster vaccine 

in HIV-infected individuals, regardless of CD4 count, since there are no data on safety, 

immunogenicity or efficacy in those individuals. There will be data in about a year from an 

ongoing study. Currently there is a yellow bar for other risk groups, but Dr. Mootrey 

proposed leaving that portion blank until there could be further discussion. 

 There were some general changes to enhance the footnotes, based on the harmonizedschedule discussion last year. There is a lot of explanatory language in these footnotes, 

particularly to describe the indications for use of vaccine. Contraindications are noted by the 

red bars on the schedule. Several of the vaccine footnotes contained language about 

contraindications during pregnancy, and that language was removed for those vaccines. For 

each of the footnotes, a URL has been added that links directly to the vaccine-specific ACIP 

statement. 

 The Tdap footnote has been revised to highlight the general statement regarding 

replacing only one Td with Tdap, just by reordering the footnote wording. The pregnancy 

language in HPV was taken out and language was added to indicate that HPV vaccine is not 

specifically indicated, based on the medical conditions mentioned in the Medical and Other 

Indications table. 

 At the opportunistic infection meeting mentioned earlier, the group did not want to 

give the impression that HPV vaccine was actually recommended for HIV-infected adults, 

even though it is not contraindicated. The footnote in the schedule also indicates that efficacy 

and the immunogenicity may be lower in certain persons. The new language for HPV says, 

"HPV vaccination is not specifically recommended for females with medical indications 

described in the table 'Recommended Adult Immunization Schedule by Vaccines That May Be 

Indicated for Adults Based on Medical and Other Indications.' Although, because it is not a 

live virus vaccine, it can be administered. However, the immune response and vaccine 

efficacy might be less than that in persons who are immunocompetent or who do not have the 

described medical indications." 

 MMR also had the contraindications language for pregnancy, and that has been 

removed. 

 The varicella footnote has been revised to indicate the use of single-antigen varicella 

vaccine. A phrase regarding an epidemiologic link to a laboratory-confirmed case has been 

added as a requirement for evidence of immunity in a healthcare-provider diagnosis of a mild 

or atypical case, and pregnancy language has been removed. 

 For pneumococcal vaccine, to be consistent with the Medical and Other Indications 

schedule heading, chronic alcoholism and chronic cardiovascular disease have been added to 

the text. CSF leaks was deleted from the immunodeficiency column and added to the 

footnote text. In the footnote for revaccination with pneumococcal vaccine, the listing of the 

multiple immunodeficiency conditions has been deleted. 

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23

 For hepatitis A vaccine, the schedules for the two single-antigen vaccines have been 

clarified. Single-antigen formulations should be administered in a two-dose schedule, and the 

specific vaccine based on which schedule was being used has been added. For hepatitis B, 

persons who receive clotting factor was removed as a risk group. For meningococcal 

vaccine, the footnote now clarifies that persons who remain at increased risk as opposed to 

high risk for infection may be indicated for revaccination. 

 A new footnote has been added for herpes zoster vaccine stating that the vaccine is 

recommended. "A single dose of zoster vaccine is recommended for adults 60 years and 

older whether or not they report a history of herpes zoster and persons with chronic medical 

conditions may be vaccinated unless the contraindication or precautions exist for their 

condition.” In the next iteration, more wording may be added. 

 A new footnote was added to address the growing list of immunocompromising 

conditions. It says that inactivated vaccines are generally acceptable and live vaccines are 

generally avoided when there are immune deficiencies or immune-suppressive conditions. 

For guidance relating to specific conditions, refer to the general recommendations, giving the 

URL and the specific pages and the table that describes immunocompromising conditions. 

Discussion

 Dr. Gilsdorf said that the inclusion of "recommended" leaves the impression that 

everything in the yellow bar is a recommendation for the use of these vaccines, but for 

chronic disease indications, HPV and Zostavax are not recommended. She suggested adding 

a different color or texture to those yellow bars that indicate that it is acceptable to use it, but 

not specifically recommended. Dr. Baker added that if that were done, one would have 

recommend Tdap in pregnancy, which the ACIP does not do. 

 Dr. Hull asked if people over 60 should get zoster vaccine rather than varicella. Dr. 

Mootrey replied that they would not if they have never had varicella. Dr. Hull added that the 

footnote on the yellow bars on both tables should be re-examined regarding the addition of 

"or." For example, one would not recommend zoster for healthcare workers younger than 60. 

 Dr. Neuzil expressed confusion about the bars for HIV and zoster or HPV, since they 

did not seem to reflect existing ACIP recommendations. Dr. Mootrey explained that the new 

language for HPV was consistent with ACIP recommendations because, for HIV-infected 

individuals, it is neither recommended nor contraindicated. Zoster vaccine is not specifically 

recommended, but it may be considered. Dr. Neuzil recommended pulling out the zoster 

statement if there had been no specific discussion on CD4 count and HIV. 

 Dr. Schuchat thought that when ACIP considered the zoster statement, HIV studies 

were ongoing. Although there is a lot of interest among the HIV providers and patients in 

getting this vaccine, more information will be forthcoming and perhaps ACIP should wait to 

make a full statement. A second issue was an inconsistency in the varicella upper-age group. 

Providers might be confused whether to give varicella or zoster or both if the patient is 65. 

One of the footnotes talks about evidence of immunity to varicella being ‘born before 1980’, 

so that it would not make sense to have this upper-age group. 

 Dr. Treanor thought that the issue about whether to screen people for evidence of prior 

immunity to varicella before giving them zoster vaccine had come up and the committee had 

decided that that was not necessary. But if it was known that someone was not immune, they 

should receive varicella vaccine. In another discussion, since there is only a small number of 

HIV-infected individuals who are 60, the issue was not so much the recommendation but 

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24

whether it will be considered a contraindication. He also recalled a discussion of the fact that 

varicella vaccine is relatively safe in individuals who are immunosuppressed, including those 

with advanced HIV, and that HIV with a CD4 count of over 200 is not a contraindication in 

the FDA label. 

Dr. Pickering observed that the recommendation for MMR says it can be given to 

HIV-infected children with CD4-positive counts above 15 percent. Varicella can be given to 

that same group, but MMRV is not recommended. The zoster vaccine has 14 or 15 times the 

amount of varicella, and a recommendation with no data is worrisome. Dr. Treanor added 

that this was a vaccine being administered to people who were already immune to the vaccine 

virus. 

Vote

 Dr. Abramson asked whether the committee was comfortable voting on the 

recommended schedule, given that the comments and suggestions would be dealt with. 

Dr. Hull moved to accept, realizing there would be minor modifications per the discussion. 

Mr. Beck seconded the motion. 

 

Dr. Lieu : yes. 

Dr. Morita : yes. 

Dr. Neuzil: yes. 

Ms. Stinchfield: yes. 

 Dr. Treanor: yes. 

 (Dr. Abramson noted that clarification was needed whether Dr. Treanor could vote. 

Dr. Pickering said he would find out and correct the minutes accordingly.) 

 Dr. Morse: yes. 

 Dr. Abramson: yes. 

Dr. Allos: yes. 

Dr. Baker: yes. 

 Mr. Beck yes. 

 Dr. Gilsdorf: yes. 

 Dr. Hull: yes. 

Dr. Lett: yes. 

PROPOSED REVISIONS TO THE CHILDHOOD-ADOLESCENT SCHEDULE FOR 

2008 

Dr. Julie Morita, ACIP WG Chair 

Dr. Angela Calugar, CDC/NCIRD/DVD

Dr. Calugar’s presentation was for information and discussion only, since it is still a 

work in progress. She showed the current recommended immunization schedule for ages zero 

through six years and the one for 7 to 18 years, as well as for catch up. The format was based 

on focus-group discussions conducted last year. Feedback on the current format for 2007 

came from participants at the National Immunization Conference and the NIP info hotline of 

the CDC. Providers say it is easier to read, convenient to print, and useful to separate age 

groups. The colors are harmonized with the adult schedule, however the green catch-up bars 

were said to be confusing. The immunization providers claimed that the content of the 

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25

Childhood-Adolescent Schedule for 2007 is clearer, the footnotes are useful and it has the 

correct level of detail in comparison with prior schedules. 

 Suggestions on how to improve the schedule were related to the hepatitis B vaccine 

birth dose, and clarifications for PCV indication, for the zero-to-six schedule and catch-up. 

More details for children with special medical conditions would be helpful. Options for 

black-and-white copies would also be very useful, as would the use of brand names, which is 

normally avoided as much as possible. 

The work group analyzed the accumulated information and conducted a joint meeting 

with the adult immunization schedule work group, which has experience with the best 

approaches for persons with special medical conditions. After a discussion about 

synchronizing the timing of the two schedules, it was decided to adhere to the existing time 

lines, i.e., the adult group will publish in October, and the childhood group will present final 

drafts in October for the ACIP vote and publish in January next year. Discussing and 

providing feedback for a draft immunization schedule for HIV-infected children ages zero to 

six years was another activity reported by the ACIP Childhood-Adolescent Schedule 

workgroup. 

 The process of updating the current schedule took into account other new vaccines that 

had been approved or were being considered by FDA. Sometimes there are new indications 

for existing vaccines, such as a potential recommendation for a younger age group for FluMist 

vaccine starting with the 2007/2008 influenza season (pending FDA decision). 

 Dr. Calugar showed the current schedule for ages zero to six years and pointed out that 

there were yellow bars for recommended ages, green for catch-up immunization, and purple 

for certain high-risk groups. Since providers find the green bars confusing and redundant, the 

hepatitis B series and Hib vaccine green bars will be removed. 

 Dr. Calugar then showed the current schedule for ages 7 through 18 years. ACIP will 

be voting on an updated recommendation for Menactra vaccine (MCV4), which would change 

the indications on the schedule. Previously it was presented as a yellow bar for a range of 

recommended ages up to 11 or 12, then for certain high-risk groups and yellow for 15-yearolds. Now there will a green bar in the catch-up immunization schedule for ages 13 through 

18, which will make MCV4 consistent with the other two adolescent vaccines -- Tdap and 

HPV series. 

The current catch-up schedule is divided, with ages four months through six years at 

the top and ages 7 through 18 years at the bottom. In all current schedules, the footnotes are 

bulleted. The minimum age for administration is on the first line for each vaccine, and the 

updated references are included. 

 In the footnotes for age groups zero through six years, the work group proposes 

adding, "For additional details, see catch-up immunization schedule." 

 Regarding the wording for the hepatitis B birth dose, if the mother is HBsAG 

negative, the birth dose can be delayed in rare cases with a physician's order and a copy of 

the mother's negative HBsAG laboratory report in the infant’s medical record. 

 The third and the last change proposed is for pneumococcal conjugate vaccine 

wording. "Administer PCV at ages 24 to 59 months in certain high-risk groups," and then 

add, "Consider catch-up for other children aged 24 through 59 months." 

 The proposed changes to the footnotes for the age group 7 through 18 years were 

simple. The group suggested adding a statement saying, "Catch-up bars highlight the 

importance of the adolescent platform. For additional details, see catch-up immunization 

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26

schedule." 

For the catch-up schedule, the PCV wording will be updated. "Administer PCV at ages 

24 to 59 months in certain high-risk groups. Consider catch-up for other children aged 24 to 

59 months." And then, as stated, "Vaccine is not generally recommended for children aged 

older than five years." 

 Updating the immunization schedules requires multiple activities, and the work group 

recognizes the importance of the feedback from immunization providers, collaboration with 

different ACIP work group and subject-matter experts, and harmonization with the 

stakeholders and the childhood and adolescent schedule. 

 

Discussion

 Ms. Stinchfield asked to change the wording in the footnotes regarding the hepatitis B 

dose from “physician order” to "provider order," because many people write orders in birth 

centers. 

Dr. Whitley-Williams, National Medical Association, was confused about whether 

children who received the meningococcal conjugate vaccine at 11 to 12 years should be 

revaccinated five to seven years later when entering a dormitory in college. Dr. Messonnier 

responded that the current thinking was that the duration of protection would be long enough, 

and the ACIP recommendations for the MVC4 were based on that assumption. However, that 

will continue to be monitored. 

 Dr. Abramson said he understood from David Salisbury that the only problems noted 

in England have been in those who were immunized before one year of age and that they have 

not seen breakthrough cases in the other age groups to date. Dr. Messonnier said the U.K. 

vaccines were mening C conjugate vaccines and each of these vaccines is slightly different. 

However, based on the U.K. experience, one would anticipate that children vaccinated at age 

11 would still be protected as they get to college. In the U.K., studies carried out before they 

began vaccinating suggested that children would be protected because they had memory, but 

the U.K. data suggest that, at least in infants, memory is not sufficient to provide protection 

without a booster dose. 

 Dr. Abramson commented that this also relates to the issue of reimmunization, which 

needs to be consistent on both the adult and adolescent schedules. 

 Dr. Wexler, Immunization Action Coalition, was concerned about the catch-up 

language for PCV, which says to administer PCV at ages 24 to 59 months of age in certain 

high-risk groups. That language is left over from the original ACIP recommendations in 2001, 

where the high-risk groups who were 24 to 59 months old were not covered by the 2-, 4-, 6-, 

and 12-month recommendations. They were written to catch the older kids in high-risk 

groups so they wouldn't not get vaccinated. She wondered why there was still a need to talk 

about certain high-risk groups, when these children should have already been vaccinated at 2, 

4, 6, and 12 to 15 months. Basically, the wording should say that all children should be 

caught up, up to age five. Dr. Calugar replied that this was consistent with the last ACIP 

recommendation on PCV. There are always a few children being seen for the first time, such 

as an adopted child, so there has to be catch-up guidance for providers. The aim was to have 

only routine recommendations in the schedule and then refer everyone to the catch-up 

schedule. 

 Dr. Wallace reminded the group that when PCV was first recommended, the language 

about catch-up in those older than two was softened, but right now it does reflect the 

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27

recommendation. Dr. Lett felt it would be important to standardize these recommendations 

for revaccination and catch-up between the adult and the childhood schedule. Moving back to 

meningococcal, she said she recalled that the revaccination statement excluded those living in 

dormitories. 

Dr. Decker reported that as far as he knew there were no definitive data anywhere in 

the world on the duration of protection from any conjugate meningococcal vaccine. From 

clinical trials, there are some published data showing the lead and rechallenge of children who 

were immunized at two to three years of age and children four to five years of age. They still 

had significant elevations of antibody, and they responded briskly and with large rises to 

challenge. The U.K. had a problem with breakthrough cases in young children who were 

vaccinated on a 2-3-4 schedule, suggesting, perhaps, a problem with that schedule and the 

need for a booster. In contrast, the Netherlands implemented a nationwide 0- to 19-catch-up 

program and routine immunization at 14 months of age, and they have had no breakthrough 

cases in anyone vaccinated in six years. They are not going to give any boosters until they see 

epidemiologic evidence of a need to do so. 

 Dr. Schuchat pointed out that the apparent inconsistency between the childhood and 

adult recommendation was not an inconsistency. The revaccination comments in the adult 

recommendation were for those who receive meningococcal polysaccharide, and those are 

high-risk adults, e.g., asplenic or working in labs. Dr. Abramson added that he had asked for 

clarification whether it was the polysaccharide followed by the conjugate. 

Dr. Baker noted that Menactra was licensed on a correlate of immunity, and that she 

understood that postlicensure a cohort of adolescents and young adults would be followed for 

duration of serologic protective correlate.

CDC IMMUNIZATION SAFETY OFFICE UPDATE

Karen Broder, CDC/ISO

Dr. Broder provided an overview of the Immunization Safety Office (ISO) program, 

described the proposed ISO research agenda development plans, and presented some 

preliminary key research themes identified during an ISO external scientific consultancy 

meeting. The mission of the ISO is to assess the safety of vaccines received by children, 

adolescents, and adults. It works closely with partners nationally and internationally to 

develop, provide, and support high-quality research in the field of vaccine safety in order to 

identify adverse events after vaccination and to assess causality and risk factors. In addition, 

it strives to communicate its work in a clear and transparent manner and to develop scientific 

methodology and standardize case definitions for vaccine adverse events. 

 Four main research and surveillance components work together to accomplish this 

mission. VAERS is an early-warning, national, passive surveillance system. It identifies 

vaccine safety signals of potential concern and generates hypotheses. The Vaccine Safety 

Datalink project or VSD is a collaboration between CDC and eight managed care 

organizations with comprehensive medical and immunization histories of about 5.5 million 

people per year. VSD tests hypotheses suggested by signals or expert review and also 

conducts vaccine safety surveillance. The Clinical Immunization Safety Assessment (CISA) 

network is a collaboration between CDC and six academic centers with vaccine subjectmatter experts. CISA strives to study the pathophysiology of adverse events following 

immunization and identify risk factors, including host risk factors associated with adverse 

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28

events, and also develops evidence-based guidance for clinicians around vaccine safety issues. 

The global Brighton Collaboration standardizes case definitions and provides a common 

vocabulary for vaccine safety research and surveillance. ISO also collaborates on a daily basis 

with other CDC programs and the FDA. 

 In October 2006, ISO conducted an internal peer review to determine whether the 

program activities were achieving the mission and identify areas for improvement. 

Preliminary conclusions were that ISO should strive for transparency, clearly identifiable 

research priorities, scientific credibility, enhancement of existing collaborations, and 

identification of new partnerships. In addition, the office needs to ensure that it can perform 

core public health functions under both routine and emergency situations. Peer reviewers 

recommended that the development of the ISO research agenda should include input from 

stakeholders in immunization safety and an external review. 

 In February 2005, the Institute of Medicine released a report titled "Vaccine Safety 

Research, Data Access, and Public Trust," which recommended that a subcommittee of the 

National Vaccine Advisory Committee (NVAC) review and provide advice on the Vaccine 

Safety Datalink research plan. In response, the Immunization Safety Office is developing a 

comprehensive, scientifically robust research agenda with extensive internal and external 

input, in three phases over a three- to five-year horizon. 

 In the first phase, CDC is already developing a draft ISO research agenda. In the 

second phase, the National Vaccine Advisory Committee will facilitate a scientific review of 

the draft ISO research agenda and provide advice, and in the third phase, CDC will respond to 

the feedback from the NVAC process and finalize the ISO research agenda. 

 CDC, the National Vaccine Program office (NVPO), and NVAC are currently 

discussing the approach for the Phase 2 NVAC scientific review, and plans have not been 

finalized. It is anticipated that this review would include a broad group of stakeholders in 

immunization safety as recommended by the Institute of Medicine. 

 To develop this draft ISO research agenda, ISO conducted an external scientific 

consultancy and also plans to obtain input from CDC programs outside ISO, other HHS 

agencies, the Department of Defense, and various nonfederal partners. Input from ACIP 

members will be welcomed through the CDC-ACIP working-group liaisons. 

 The charge to the individual external scientific consultants was to identify emerging 

vaccine safety research questions not currently being addressed, propose potential approaches 

to study each question, and advise on prioritization of research topics. Seven consultants 

were invited, representing the fields of pediatric infectious diseases, adult infectious diseases, 

OB/GYN, immunology, genomics, and epidemiology. In addition, there were liaison 

representatives from Federal agencies, advisory committees, CDC research collaborations, 

and the ISO, as well as the Office of the Chief Science Officer, CDC. 

 The framework used to guide brainstorming discussions was the five life stages: 

infants, children, non-pregnant adolescents, non-pregnant adults, and pregnant women. 

Cross-cutting categories included the role of public perception in shaping the ISO research 

agenda, considerations for vaccine safety surveillance, safety of non-antigen vaccine 

constituents and new vaccine technologies, and adverse events that occur years after 

vaccination. Six consultants also presented their own perceptions of the most important 

vaccine safety topics.

 During the brainstorming sessions, consultants thought broadly about vaccine safety 

research without considering infrastructure or programs. Some of the topics that emerged are 

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29

already being addressed in a current research activity, or might be more appropriate for other 

CDC or HHS programs, for example, studies of risk perception around vaccination. 

 The ISO is compiling a report that summarizes the full spectrum of the independent 

advice that consultants provided, but there were some key themes that appeared most relevant 

to the future ISO safety research agenda. One was the need to better understand the 

relationship between certain host risk factors and vaccine adverse events. These factors 

include prematurity and low birth weight infants; the influence of gender on vaccine adverse 

events; pregnancy; aging; the presence of chronic conditions, including diabetes; as well as 

genetic factors. 

 Another key area was vaccine-specific safety. In the case of rotavirus and LAIV, the 

concern was for a specific adverse event: intussusception for rotavirus vaccine and wheezing 

after LAIV. But influenza vaccine was of general interest because of the need for pandemic 

influenza preparedness. HPV was highlighted for a variety of reasons, including public 

sensitivities about giving the vaccine to adolescent girls widely. Tdap and zoster were listed, 

in part, because of safety issues regarding off-label use outside the licensed age range. 

 Other specific reported vaccine adverse events were included for different reasons. 

Some, like intussusception, are of concern following a particular vaccine (rotavirus), whereas 

Guillain-Barré syndrome and demyelinating disorders are of general interest. In addition, 

with increasing focus on adult vaccination, consultants identified a need to understand the 

incidence of cardiovascular disorders. 

 Of the other research topics that emerged during the meeting, some are relevant to the 

ISO research agenda, and some may also be relevant to other research agendas. Topics 

included the role of novel vaccine adjuvants, which is coming up in an HPV vaccine currently 

in the pipeline; understanding immune mechanisms for vaccine adverse events; and 

strengthening surveillance for reported vaccine adverse events, including signal detection. 

Understanding age-specific baseline rates of conditions reported as adverse events was a high 

priority. Off-label use of vaccines was another important area, for example, use of LAIV in 

persons with conditions that place them at increased risk for influenza complications. 

 Next steps are to work with the individual consultants to complete the consultancy 

report, gather input from the other vaccine safety partners, and develop a draft ISO research 

agenda that can be shared with NVPO and NVAC for the scientific review. 

 

Discussion

Dr. Treanor asked whether there had been any interest in exploring the genetic basis of 

vaccine side effects. Dr. Broder replied that it is such a new area in vaccine adverse event 

research that detailed discussion was outside the realm of this particular consultancy. Dr. 

Iskander said his office had been funded by NVPO to conduct a separate meeting on this 

general topic, recognizing the emergence of data and interest. They will be seeking 

collaboration and input and hope to have the meeting early in the first quarter of 2008. 

Dr. Katz asked why NIH was not in the list of federal agencies with liaison 

representatives to the ISO external scientific consultancy. Dr. Broder replied that the liaisons 

represented at the consultancy were there to hear the presentations, understand discussion and 

provide technical background. As recommended by IOM, there will be multiple stakeholders, 

including the other HHS agencies, in the NVAC review. The ISO is collaborating with 

NVPO to obtain input from the other federal agencies as the preliminary research agenda is 

being drafted, which would include colleagues in the FDA and NIH, as well as other federal 

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30

agencies. 

UPDATE: HERPES ZOSTER VACCINE SAFETY

Dr. John Treanor, ACIP WG Chair 

Dr. Sandra Chaves, CDC/NCIRD/DVD

Dr. Treanor noted that as of January 2007 approximately 350,000 doses of zoster 

vaccine had been administered. It is complicated but interesting to look at adverse events in a 

population with many concurrent medical events. 

Dr. Chaves reminded the committee that the vaccine was licensed in May 2006, and 

by October, it was recommended for adults age 60 years and older. Injection-site reaction 

was the main adverse event reported during clinical trials, and it was clearly more frequent 

among those receiving the vaccine. There were no other clinically important or statistically 

significant differences observed regarding systemic or serious adverse experiences. However, 

in the adverse event monitoring substudy, where approximately 6,000 people were closely 

followed, the rate of serious adverse events was higher among those receiving the vaccine 

compared to those receiving placebo, but no clinical pattern was identified. 

 This safety update was based on data from VAERS, which uses a coding system to 

computerize reported events and as a way of standardizing complaints. A report is classified 

as serious if a patient reported having been hospitalized or if the patient died or had any lifethreatening or disabling illness or any other medically important condition. 

 VAERS received 590 reports through June 1st, which represents an overall reporting 

rate of 73.3 per 100,000 doses distributed. These rates are based on preliminary data provided 

by the manufacturer. Among those, 44 reports were characterized as serious, for a reporting 

rate of 5.5 per 100,000 doses. Two were deaths. 

 Among the 590 reports, over half were women, and for reports classified as serious, 

43 percent, 19 out of 44, occurred among those ages 70 to 79 years. It is important to note 

that 14 percent of all reports represented people younger than 60 years. This younger group 

would represent off-label use or administrative error; many were children under five, and 50 

percent were adults aged 21 to 59. In 90 percent of the reports, Zostavax was administered 

alone. The others referred to concomitant administration of other vaccines that were part of 

the childhood immunization program. 

 The most common adverse events were injection-site reaction, rash and zoster. The 

majority were female and the median age was 65 to 68 years. The interval between 

vaccination and event onset was a median of one day for injection-site reaction, three days for 

rash, and five days for zoster. The interval ranged from less than one day to eight to nine 

months or up to a year for rash. None of the zoster cases tested so far has been confirmed to 

be due to Oka strain, but very few have actually been tested. 

There were reports of allergic reactions and anaphylaxis occurring soon after 

vaccination. Although hospitalization was required, which automatically classified these 

reports as serious, they offered very good outcomes. 

 One pregnant woman was inadvertently vaccinated with Zostavax; the patient actually 

requested to be vaccinated and then, ten days later, was found to be pregnant. She is being 

followed by the pregnancy registry, but there is no further information on pregnancy outcome. 

There were three cases of encephalitis. One started with disorientation within the first 

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31

24 hours of vaccination. The MRI did not show any abnormalities, and CSF was negative for 

herpes simplex, but no test was done for VZV. The other two encephalitis cases had very 

limited data available. 

 Eight events were coded as secondary transmission, five of which were reports of 

people developing zoster after being exposed to a spouse who had been vaccinated with 

Zostavax. Of the other three, one was a child who was exposed to his grandparents and 

developed chickenpox a few days later. A man was exposed to his wife who had been 

vaccinated with Zostavax, and ten days later he developed chickenpox, but it is unlikely that 

his chickenpox was a result of this exposure. There was also a physician who was exposed to 

a patient who had zoster after being vaccinated; two weeks later, she found two vesicles that 

she assumed could be chickenpox and started antiviral treatment, even though she had a 

history of chickenpox during childhood. 

 Some of the events were coded as varicella and varicella post vaccination. Eleven 

were varicella-like rash occurring after vaccination with Zostavax, with one case hospitalized 

due to the extent of the rash, but no lab data are available for any of these cases. Four reports 

classified as varicella post vaccination were actually zoster. Among the zoster cases, there 

was a 63-old-woman hospitalized with acute retinal necrosis and zoster in her right eye, but 

no further lab information was available. 

 Most of the events coded as medical error or wrong drug administered were presented 

as human error or unintentional use of Zostavax instead of other vaccines, such as Varivax 

and ProQuad. There were two reports of immunosuppressed individuals who were 

inadvertently vaccinated, and two reports of local injection-site reactions in persons under age 

60, which could represent off-label use. 

Two deaths were reported as temporally associated with the receipt of the zoster 

vaccine. Both persons were 80 or older, but clinical-lab information was not available. For 

one of the cases, the cause of death was sepsis and pneumonia, occurring six months after 

vaccination. The other had a heart attack a week after vaccination. 

 To summarize, Zostavax seems to have a very good safety profile, very much as 

expected during clinical trials pre-licensure. The most frequent reported event is injection-site 

reaction, although herpes and rash were very common. There is no way to establish any 

association with the vaccine virus without support of laboratory information. It is also 

possible that all the zoster captured in the system was a reflection of vaccine failure since 

vaccine efficacy was around 60 percent. Many of the reports describe events related in time, 

but that is likely caused by other factors, especially in this age group, where co-morbidity is 

common. 

 Surveillance is extremely challenging for this vaccine. VAERS is a good system for 

providing signals, but a better understanding of administration errors and off-label use of the 

vaccine will come from specific studies. VAERS data are passive surveillance, subject to 

underreporting, lack of clinical and laboratory information that would establish causality, and 

lack of denominator data. Post-licensure safety studies are expected to be undertaken, which 

would add to the safety profile of the vaccine. CDC, through the Vaccine Safety Datalink and 

Kaiser Permanente and Group Health Cooperative, will look at adverse events among adults 

50 years and older. This cutoff age may provide a better assessment of off-label use of the 

vaccine. Also, Merck has agreed to conduct a post-licensure, randomized, placebo-controlled 

clinical trial in approximately 12,000 subjects, where half will be receiving the vaccine and 

the other half placebo. They will also assess the use of high-potency doses of Zostavax and 

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32

the use of lower doses for people taking corticosteroids. 

 

Discussion

 Dr. Allos noted that 34 of the administration errors involved children who were 

supposed to be receiving Varivax. She wondered if those were all in just a few sites or if they 

were randomly distributed, whether packages looked similar, and whether anything could be 

done to make them look more distinctive. Dr. Chaves responded that packaging and labeling 

did not seem to be the major issue in the reports. It was really just unintentional, human 

mistakes. She did not have any information about how many sites were involved. 

Dr. Pickering commented that when meningococcal conjugate vaccine first came out, 

it was inadvertently given subcutaneously instead of intramuscularly as was recommended. 

However, a study of about 100 people who had blood drawn showed the titers were low but 

still acceptable, and they did not need to be immunized again. He wondered what the 

recommendation would be for children who get this vaccine, at 14 times the dose of Varivax, 

with regard to a second varicella immunization. Dr. Chaves replied that there was no official 

recommendation. A two-dose recommendation was in place for varicella, and one would 

need to assess if a higher dose was as efficacious as a two-dose vaccination. Dr. Kuter from 

Merck added that they had actually looked at material as high as 50,000 platform units in 

healthy children and safety was comparable to their typical dose in the five to 10,000 dose 

range PFU. However, there was a plateauing of the response, i.e., the seroconversion rates 

and GMTs were comparable whether children were given 5,000 or 50,000 PFU. Off label, she 

still recommended that a second dose be given. 

COMBINATION VACCINES

Patricia Stinchfield, RN, MS, CPNP, ACIP WG Chair 

Ms. Stinchfield explained that the combination vaccine working group (WG) was 

reinstated to develop a revised statement on the use of combination vaccines for review and 

approval of the ACIP. The last statement was written in 1999. The long-term goal is to 

review issues surrounding the availability and use of combination vaccines. However, an 

important and immediate short-term goal was to review an upcoming vaccine known as 

Pentacel®, a DTaP-IPV-Hib combination vaccine, in anticipation of discussion at a future 

ACIP meeting, pending the FDA approval. 

 Sanofi pasteur submitted the BLA for a four-dose primary series in children for the 

two-month, four-month, six-month, and 15- to 18-month part of the schedule. The FDA 

requested additional information from sanofi, which resulted in an extension of the review 

clock for this BLA. Pentacel® was approved in Canada in 1996 and in all the jurisdictions by 

'97, '98. Canada has had an excellent experience with this vaccine, and any future detailed 

presentation will include the Canadian experience. 

 Beginning in April, the WG met weekly by conference call. The WG conducted an 

overview based on the VRBPAC presentation and looked at the immunogenicity of the 

vaccine's components. The Canadians presented their experience with Pentacel®, which is 

now used exclusively there. 

 The WG talked with the Committee on Infectious Disease about harmonization and 

the future recommendations in agreement with what is already published in the Red Book. 

There was also discussion about implementation for special risk populations, such as 

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33

American-Indian and Alaskan-native children, and some of the nuances that will have to be 

considered for Pentacel® in the childhood immunization schedule. 

 Future topics for the WG, pending FDA licensure of the vaccine, will be a detailed 

presentation at the October ACIP meeting on Pentacel-related topics. Work will continue on 

the draft of the MMWR notice to readers, to be presented for discussion most likely at the 

February 2008 meeting. Then, pending FDA licensure and ACIP recommendation, there 

would be an ACIP vote on inclusion of Pentacel in the VFC program. 

 Other future topics would be to review and prepare communications regarding 

combination vaccines new to the market. For example, GSK recently indicated that the FDA 

has accepted the BLA for their DTaP-IPV, which is a pediatric booster vaccine for 

immunizations against diphtheria, tetanus, pertussis, and polio at the four- to six-age group. 

 The WG will continue work on updating the MMWR statement on combination 

vaccines that was written in 1999. Issues will be reviewed surrounding the availability and 

use of combination vaccines in the current U.S. market, after which the statement will be 

revised and there will be a discussion about whether to incorporate the combination vaccine's 

topic into the general recommendations document. Ms. Stinchfield invited members to offer 

other agenda items. 

Discussion

 Dr. Decker explained that Pentacel® was delayed because the manufacturer moved its 

global pertussis laboratory testing facilities into the United States. In association with that, 

FDA CBER wanted to review all the comparability data with the existing files for all of the 

pertussis products, so licensure of Pentacel® has been held up until they finish reviewing the 

lab validation data. 

UPDATE: MENINGOCOCCAL CONJUGATE VACCINE (MCV4)

Dr. Carol Baker, ACIP WG Chair 

Dr. Amanda Cohn, CDC/NCIRD/ISD

Dr. Ismael Ortega-Sanchez, CDC/NCIRD/DVH

Dr. Phil Hosbach, sanofi pasteur 

Dr. Gregory Wallace, CDC/NCIRD/ISD

Dr. John Iskander, CDC/ISO

Dr. Baker explained that the ACIP MCV4 recommendations were first published in 

May of 2005, recommending vaccination of the following groups: persons aged 11 to 12 

years, adolescents at high-school entry, and other persons at increased risk of invasive 

meningococcal disease, including college freshmen living in dormitories. This three-cohort 

list was based on supply and risk considerations. The peak of disease in adolescents begins 

around entry to high school, and there are strong data on college freshmen living in 

dormitories, but there was a desire to start immunizing the 11-to-12 cohort as well. This was 

the first vaccine to go forward, quickly followed by Tdap and HPV, the major tenets of the 

adolescent platform. 

 Then there was a supply-demand issue, so an MMWR notice in May 2006 deferred the 

11- to 12-year-olds because they were at baseline level of risk. When supply became abundant 

again, an October MMWR notice told people to resume the 11- to 12-year-old 

recommendation, but this was not well implemented. There is currently an excess supply. 

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34

Epidemiology 

Dr. Cohn provided an overview of the current epidemiology of meningococcal 

disease in the United States, including recent trends and the burden in adolescents and young 

adults. The national passive surveillance system, known as NETSS, receives case reports 

from all 50 states and provides the numbers seen in the MMWR. ABC is an active laboratory 

and population-based surveillance system composed of ten sites in the U.S. Their data are 

important for serogroup and additional clinical information on cases. 

Data on the incidence of meningococcal disease in the United States from 1970 to 

2005 show a cyclical waxing and waning pattern with peaks every eight to ten years. The 

case-fatality rate decreased in the 1970s but has remained between 5 and 10 percent since the 

1980s. Since 1996 incidence of meningococcal disease has been on a downward cycle. 

Serogroups B, C, and Y each cause approximately one-third of meningococcal disease in the 

United States. Since 2002 Serogroup B has caused the highest disease incidence, but there is 

currently no vaccine available in the U.S. that protects against that disease. 

 Rates of meningococcal disease are highest in infants under one year and remain high 

in one- to four-year-olds, age groups for which there is currently no effective vaccine. 

Seventy-five percent of vaccine-preventable cases are in persons 11 years and older. 

 The 2005 MCV4 recommendations were made to impact the second peak in 

adolescents, who have the greatest burden of disease among the age groups for which MCV4 

is currently licensed. Disease incidence increases through adolescence, peaking in 18-yearolds. Although the duration of protection from MCV4 was unknown, it was anticipated that 

when given to 11- and 12-year-olds, the vaccine would remain effective through late 

adolescence. The vaccine was also recommended at high-school entry to correspond to the 

rising risk. 

 Most cases of meningococcal disease occur in previously healthy children and young 

adults. Case-fatality rates among adolescents and young adults are higher than among 

children less than ten years old and above the overall case-fatality rate of 12 percent. 

Achieving high coverage with MCV4 could prevent up to 75 percent of cases in 11-19 year 

olds. Among children four years old and under, around 50 percent of cases would be vaccine 

preventable if a quadrivalent or CY conjugate vaccine were available. The majority of cases 

in infants are caused by Serogroup B. 

 In conclusion, meningococcal disease incidence is currently at the nadir of its normal 

cyclical disease pattern. Despite implementation of the MCV4 recommendations in 2005, the 

CDC does not believe the vaccine has impacted current disease trends. Meningococcal 

disease continues to be a significant cause of morbidity and mortality among adolescents in 

the United States. Serogroup B vaccines and safe, effective vaccines for infants will be 

needed to achieve meningococcal disease control in the United States. Vaccinating all 

persons aged 11 to 18 years with MCV4 would have a substantial impact on disease in this 

age group. CDC is conducting vaccine effectiveness and carriage studies and will continue to 

use active surveillance to monitor the impact of MCV4 recommendations and the duration of 

protection. 

The Economics of Adolescent Meningococcal Vaccination in the U.S.: Direct and 

Indirect Protection

Dr. Ortega-Sanchez talked about the economics of expanding the adolescent 

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35

meningococcal vaccination in the U.S. using the four-serogroup conjugated vaccine. The 

objective of the study was to see whether vaccinating most adolescents could significantly and 

immediately generate herd-immunity benefits. Therefore, Dr. Ortega-Sanchez’s analysis was 

focused not only on the direct impact on adolescent vaccines, but also on the potential herd 

immunity impact in the rest of the U.S. population (the indirect impact) 

 A Monte Carlo simulation analysis model was constructed, using a one million 11- to 

17-year-old sample representative of a 10 million population cohort. The vaccination strategy 

was a one-time mass vaccination of children ages 11 to 17 years followed by routine 

vaccination of each new 11-year-old cohort. The timeframe (or time of the interventions) is 

ten years, but the health benefits and costs are measured over the age-specific life expectancy. 

The discount rate used for health costs outcomes was three percent. 

 As an illustration of the model the population was stratified into three age groups: less 

than 11 years, 11 to 17 years, and 18 years and older. Direct protection can be achieved for 

adolescents with vaccination. Vaccination also offers indirect protection and a safety net for 

other age groups who are not vaccinated or for those whom the vaccine fails to protect. In a 

ten-year period, approximately 16 of the cohorts will be vaccinated: seven cohorts in the mass 

campaign and nine cohorts of 11-year-olds routinely vaccinated in the subsequent nine years. 

 Epidemiology data included age, year, and serogroup-specific rates, and the average 

age- and serogroup-specific case-fatality ratios. The proportion of survivors with sequelae 

was also estimated using data from the literature. Initial vaccine efficacy data were taken 

from the U.K. experience with the conjugate Serogroup C vaccination program, which is in 

line with the studies of the four-serogroups meningococcal conjugate vaccine. The study 

assumed that duration of vaccine efficacy was ten years, and that vaccine coverage in 

adolescents was 70 percent, also in line with the U.K. experience. 

Age-specific incidence data were used for estimating the number of cases in the 

population and deaths were calculated using the age- and sequelae-specific case-fatality 

ratios. Cases with long-term sequelae were then calculated using the proportion of 

meningococcal survivors with specific sequelae. 

Two studies in the U.K. reported age-specific reductions in cases among the 

unvaccinated from vaccination campaigns with the conjugate Serogroup C vaccine with an 

average of 57 to 67 percent reductions (Ramsey et al. and Balmer et al.). These age-specific 

rates were used to calculate the number of cases indirectly prevented in the U.S. study. 

 Previously published estimates of direct costs were updated to 2006 by using the gross 

domestic product (GDP) deflator. It was also assumed that each active meningococcal case 

would be hospitalized. Indirect costs associated with meningococcal disease were used to 

estimate the cost of illness per case in each age group. Costs were broken down into those 

associated with the acute infectious phase of the disease and those from long-term 

complications of permanent sequelae or premature death. 

A base-case cost of $83 (range $50 to $110) per vaccinee with a single dose was 

assumed. Vaccination program costs comprised vaccine, vaccine administration, and 10 

percent vaccine wastage. Costs of adverse events were included, but time lost by vaccinees or 

vaccines’ caregivers to get the vaccine was not included. 

 Without the vaccination program, an average of 1600 meningococcal cases 

attributable to the C, Y, W135 serogroups would have been expected. The reduction in cases 

after mass vaccination in 11- to 17-year-olds in Year 1 and the routine vaccination of 11-yearolds in the following years is represented by two extreme scenarios. The first scenario is the 

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direct-protection-only scenario, with an average of 156 cases per year, representing 

approximately a 9 percent reduction. The second scenario is the direct protection plus the full 

herd-immunity protection, using the proportions observed in the U.K. with the meningococcal 

Serogroup C vaccine. This would avert approximately 835 cases per year in adolescents, 

which represents a 48 percent reduction. As seen by these estimates, almost four-fifths of all 

prevented cases are attributable to the herd immunity. 

Over a ten -year period, the mass and routine vaccination program will prevent 

approximately 8,251 cases, representing approximately 1700 complications and 700 deaths 

prevented. These reductions will result in approximately 30,000 life-years saved (15,000 

when discounted) or 69,000 QALYs saved (27,000 when discounted). 

A ten-year cost projection to the whole U.S. population found that meningococcal 

disease due to the vaccine-containing serogroups will cost approximately $1 billion in direct 

costs and $1.7 billion in indirect costs, both after discounting. Before including vaccination 

program costs, mass vaccination followed by routine immunization in subsequent years will 

save approximately $1.4 billion over ten years. At $83 per vaccinee, the mass and routine 

vaccination program will cost approximately $3.2 billion over ten years, which translates to 

about $223,000 per case averted or $2.6 million per death prevented. In assessing the costeffectiveness of a mass vaccination campaign followed by the routine vaccination program, 

the cost to society will be approximately $127,000 per life-year saved and $88,000 per QALY 

saved. 

 A previous study reported that it was more cost-effective to continue vaccinating 

adolescents than toddlers and infants. The Shepard study published in Pediatrics in 2005 did 

not include herd-immunity impact, and the vaccine efficacy was assumed to last 20 years. 

When this study was updated, with an assumption of a ten-year duration of vaccine efficacy, 

the routine vaccination program was less cost-effective than mass vaccination plus routine 

vaccination for adolescents. If the most recent data on the reduction in attack rates, those 

reported in Ramsay’s study for the U.K., are used, the societal cost drops to $116,000 per lifeyear saved or $81,000 per QALY saved. 

 Regarding indirect protection, mass vaccination followed by routine program had a net 

societal cost of $414,000 per life-year saved, assuming achievement of only 20 percent herd 

immunity as reported for the U.K. If the U.S. can reach the same reductions in attack rates as 

the U.K., the cost per life-year saved here will be $127,000. 

 Two recent studies of vaccination in adolescents have also considered herd immunity, 

one on pertussis and the other on human papillomavirus. These studies have shown a lower 

cost to society per life-year or QALY saved, which means that they are more cost-effective 

than mass and routine immunization with meningococcal conjugate vaccine in adolescents. 

 Two other studies reported cost per life-year saved with a vaccine, but neither 

included herd-immunity assumptions. The first looked at the cost-effectiveness of 

vaccinating first-year college students in dorms with the meningococcal polysaccharide 

vaccine and found that mass vaccination followed by routine vaccination would be 

approximately two times more cost-effective than vaccinating college students living in 

dormitories with meningococcal polysaccharide vaccine. The other study estimated that if the 

pneumococcal conjugate vaccine were used only to prevent meningitis in infants, the cost per 

life-year saved would be more than $300,000 (in 2006 U.S. dollars); namely, it would be 

much less cost-effective than the mass vaccination program followed by the routine 

vaccination. 

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37

 The current study has some strengths and limitations. One strength is the use of 

complex modeling, which includes direct and indirect effects of vaccination. It also explicitly 

used surveillance data for specific ages and serogroups containing the vaccine. A limitation is 

that data on vaccine efficacy and herd immunity are from the U.K. and are not specific to the 

U.S. vaccine. In addition, quality of life during the acute disease was not assessed, and the 

QALY scores used to assess the long-term complications are not meningococcal diseasespecific. 

 In conclusion, the one-time mass vaccination of healthy adolescents followed by a 

routine program of 11- to 12-year-olds could have substantial impact on the burden of disease. 

Up to 48 percent reduction of cases could be expected, and 80 percent of these reductions 

could be due to herd-immunity impact. However, it would have a net societal cost. For the 

same duration of vaccine efficacy, the one-time mass vaccination followed by routine 

vaccination could be half as expensive per life-year saved and QALY saved as routine 

vaccination of 11- to 12-year-olds only. 

 

Discussion

Dr. Neuzil asked whether it was reasonable to assume that the U.S. herd-immunity 

effects would be the same as the U.K., based on a mass-vaccination campaign of adolescents 

followed by routine vaccination. Dr. Messonnier replied that the U.K. vaccinated everybody 

under age 20. It is not clear that the U.S. would see the same impact, even for 11- to 17-year 

olds. However, that is probably where much of the transmission is coming from, which is 

why an optimistic scenario was presented. 

 Dr. Morse was curious why 11 to 17 was used rather than 11 to 18, and whether that 

would make a difference in the cost estimates. Dr. Ortega-Sanchez responded that 11 to 17 

was used for simplicity because there were approximately one million 11- to 17-year-olds in 

the 10 million population sample. This does not preclude the possibility that there will be 16 

cohorts vaccinated in a ten-year period, which will also create herd-immunity impact. 

 Dr. Treanor noted that the calculation of cost per QALY saved was first based on a 

policy that does not induce herd immunity (routine vaccination) and then based on mass 

vaccination, which does induce herd immunity. He asked whether one would save money by 

doing a mass-vaccination campaign. Dr. Ortega-Sanchez answered that when this study was 

compared with the Shepard study, assuming ten years duration of vaccine efficacy and costs 

in 2006 dollars, the cost per life-year saved for the mass and routine vaccination program was 

less than the cost per life-year saved for the routine vaccination only. Dr. Treanor further 

asked about the cost of mass vaccination plus routine vaccination per QALY saved in the 

absence of herd immunity. Dr. Ortega-Sanchez replied that it was more than $414,000 per 

life-year saved. 

 Dr. Lieu said she had the impression that mass vaccination actually meant catch-up 

vaccination for the children who did not fall in those two age bands for whom it is currently 

recommended. Even assuming zero herd immunity and that the cost per life-year saved is 

$700,000, she wondered why that was so much higher than what was seen in the original 

Shepard analysis, which assumed zero herd immunity and found something in the range of 

$200,000 per life-year saved. Dr. Messonnier explained that by vaccinating at age 11, the 

benefits are reaped for the next ten years, whereas vaccinating a 17-year-old has fewer 

benefits because the rates of disease decrease greatly after age 18. Dr. Ortega-Sanchez added 

that because most vaccination costs in the model happened in the first year and that costs 

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38

close in time usually have bigger weight than cost in the long run when discounted, the mass 

vaccination program costs have a bigger influence than in a routine programs, which are 

usually distributed over time. 

 Dr. Schaffner noted that much of the motivation for the initial recommendations came 

out of the epidemiology of meningococcal disease on college campuses and wondered if there 

were any efforts to track the occurrence of meningococcal disease in college campuses 

subsequently. Dr. Turner, American College Health, replied that there was no comprehensive 

effort to collect data, but that the number of press reports about individual cases has dropped 

over the last four or five years. He added that he had been struck by the data showing that 

Serogroup B now is more common than C and Y. This started around 1999 or 2000 when 

vaccination of these cohorts began, which seemed to imply that immunizing this group had 

not had much impact. Dr. Abramson asked what happened to B in England after mass 

vaccination in C. Dr. Messonnier replied that when they began vaccinating, 60 percent of 

their disease was B and 40 percent was C. There is currently an increase in B disease, so the 

dramatic decline in C was not related to B. 

Vaccine Supply and Demand

Dr. Hosbach of sanofi pasteur, said that after the recommendation was made in May 

2005, there was a very enthusiastic response in uptake of Menactra, as shown by claims filed 

by physicians in the private sector. Although the recommendations were targeted for three 

cohorts, there was a large response in all ages from 11 to 18, with some peaks at 14 and 18. 

This put pressure on the supply, so the CDC, ACIP and medical societies decided to 

temporarily defer 11- to 12-year-olds, after which the claims shifted to the older age 

categories. 

 With demand held down, the manufacturer was able to stock up on vaccine without 

exhausting supply. In fact, at the end of 2006, there were approximately 2 million doses in 

the warehouse and there will be twice the amount of vaccine available this season compared 

to last year. This information gave stakeholders and the working group the confidence to 

restore the recommendation to include the 11- to 12-year-olds in late 2006. From January 

through April of 2007, more children were immunized with Menactra in the private sector 

than at any other time period. So people are responding to the revised recommendations and 

getting immunized. Tdap was just being introduced during that time, and there was good 

uptake of the vaccine in 11- to 12-year-olds, but there was still a gap between Tdap claims 

and Menactra claims, which could be a hang-over effect from the deferral of 11- to 12-yearolds. 

 In 2006 sanofi pasteur sold and/or distributed 4.3 million doses and had a surplus of 

nearly 2 million doses, which was carried into this year. Projections, based upon the threecohort demand, are for an uptake of around 6.3 million doses, which would have meant a 

surplus of about 3 million doses. Over 9 million doses will be available in 2007, and in 2008 

more than 11 million doses will be available. 

 Marketing looked at low-, medium-, and high-uptake scenarios if there was an 11- to 

18-year-recommendation and everyone received one dose of vaccine. They assumed that the 

85 percent or 70 percent immunization rate would not be achieved for adolescents overnight. 

Actually, tripling or doubling the current rate in one year would be quite substantial. But as a 

cohort gets immunized over time, it shrinks. Starting with immunizing the 30 million 

adolescent cohort in 2006, by 2007 there are only 27 million to immunize if immunization 

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39

rates are achieved. By 2008, there would be 21.7 million people to immunize. Even with an 

additional demand for a million-plus doses this year, above the 6.3 million projected, there 

would still be a surplus for next year. In fact, the number of doses required for adolescent 

immunization will probably peak at around 7 to 7.5 million doses annually in the next year or 

two. Supply for January and September is on track and will exceed 6 million doses. With the 

surplus, there will be more than 9 million doses available. 

 Beyond 2007, supply is expected to continue to increase each year, but as 

immunization rates increase, the total number of eligible adolescents will decline. The market 

peak is not expected to exceed more than 7 or 7.5 million doses over the next three years. 

However, by that time there could be a recommendation or an indication for two- to ten-yearolds and this committee can consider what to do with the surplus doses. 

 

Vaccine Supply in the Public Sector

Dr. Wallace covered supply and demand in the public sector. After implementation of 

the recommendation, CDC provided allocations to the states and grantees based on their VFC 

populations. There already was an 18-year-old demand from the previous polysaccharide 

recommendation. The real demand for a new vaccine is unpredictable in the public sector. 

There was a lag in 317 and state funding, and the gap seen with all vaccines. Through the 

2005 contract, CDC purchased 1.4 million doses of MCV4 out of a total national sales of 3.1 

million doses, or 46 percent. This was lower than the 53 or 54 percent seen for all the 

pediatric and adolescent vaccines, partly due to the 11-to-12 deferral. 

 It is difficult to reach public sector adolescents beyond the age of 11 to 12. Grantees 

loose assess to some at-risk children as they go into their teenage years and the public sector 

is not the majority provider for 18-year-olds, where demand is highest. Due to that drop in 

doses used, there was actually a risk of expiration of vaccine already on the shelf. Even when 

restrictions on the 11- to 12-year-olds were removed, there was no increase in the demand for 

the vaccine off the CDC contracts. In summary, the number of doses available to the public 

sector is increasing but use is not, resulting in a risk of expiration of vaccine and missed 

opportunities for protection. 

Update: Vaccine Safety

Dr. Iskander presented a summary of post-licensure safety data for Menactra, as well 

as data on Guillain-Barré syndrome, or GBS, following Menactra, based mostly on VAERS 

data, Vaccine Safety Datalink uptake data, and planned and ongoing studies. Dosedistribution data were obtained from the manufacturer. 

 Through November 2006, a little more than 1,000 adverse event reports have been 

received for Menactra. Just over 10 percent of those met the criteria for serious adverse 

events. During the same time period, 7.5 million doses of vaccine were distributed. There is 

no routine ongoing reporting of numbers of doses administered overall or broken out by age 

group, but published data on usage of Menactra can be obtained by looking at proportionate 

use by age group and focusing on the transition from the previous polysaccharide vaccine to 

the conjugate vaccine. The overall dose-adjusted reporting rates for Menactra are 14 per 

100,000 doses and serious adverse events are just over 1 per 100,000 doses distributed. 

 Most of the reports concern the ages between 11 and 12, gender distribution is 

relatively equal, and the majority of reports involve Menactra given as a single vaccine. 

The most frequently reported symptoms involve pain. Other frequently reported adverse 

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40

events include headache, fever, myalgia, vomiting, and diarrhea. As is common with reports 

to VAERS, there was a very close temporal proximity to vaccination in the majority of 

reported adverse events. There have been 19 reports of unintentional injury related to 

vasovagal syncope. Two of the more significant injuries involved loss of consciousness 

following syncope. In addition, there were two instances of individuals who apparently 

experienced syncope while driving, although neither was reported to be injured. There have 

also been vaccine-administration errors, but data published in the September 2006 MMWR

showed no effect on immunogenicity. 

 Serious adverse events are those that involve hospitalization, deaths, disability, or lifethreatening injury with no causality inferred or implied. Three-quarters of those reports 

involved Menactra given as a single vaccine. Clinical reviewers at the FDA and CDC 

categorized them according to the primary type of event and/or organ system. Most were 

neurological in nature, with smaller numbers in a variety of other organ systems. 

 There have been two reports of death following receipt of Menactra. An 18-year-old 

male died four days after Menactra with cause of death listed as presumed cardiac arrhythmia. 

An 11-year-old developed a headache, vomiting, and abdominal pain nine days after receiving 

Menactra and subsequently became encephalopathic. His autopsy revealed acute hemorrhagic 

leukoencephalitis, a rare form of acute demyelinating encephalomyelitis. 

 As of 30 April 2007, a total of 19 confirmed Guillain-Barré syndrome cases within six 

weeks of Menactra administration had been reported to VAERS. All but two were among 11- 

to 19-year-olds with onset 2 to 33 days following vaccination. Six had received concomitant 

vaccines. Reports peaked during the summer months of the past two years. All recovered or 

are recovering at this time. 

 Comparing observed confirmed cases from VAERS within six weeks of vaccination 

stratified by age to the background rates obtained from the Vaccine Safety Datalink and 

controlling for the seasonality within the VSD, there appears to be a slightly increased risk 

among 15- to 19-year-olds. Data analyzed to date indicate that, among more than 140,000 

doses administered, zero cases of GBS have been observed within six weeks of vaccination. 

The number of expected cases, based on the background rate observed within the VSD for 

such a population, would range between zero and one. Within the VSD, 94 percent of 

Menactra recipients are within that 11- to 19-year-old age group, which also comprises the 

majority of the GBS reports. 

 Harvard Pilgrim Healthcare is undertaking a manufacturer-sponsored controlled study 

of GBS following Menactra. They propose to include a population of approximately 10 

million 11- to 18-year-olds, which would have sufficient power to detect an elevated risk 

ratio; the Vaccine Safety Datalink is not large enough to undertake such a study. The Clinical 

Immunization Safety Assessment network also continues to conduct detailed case reviews and 

focused laboratory evaluation with an eye toward studies of hosts, such as genetic risk factors. 

 For 11- to 19-year-olds overall, there is no statistically significant evidence of an 

increased risk of GBS after Menactra vaccination, but there does appear to be an increased 

risk within the 15- to 19-year-old age category. However, this has to be put in the context of 

the inherent limitations of VAERS and the uncertainty regarding the background rate within 

the VSD. The timing of neurologic symptoms, which has been consistently within one to five 

weeks following vaccination among reported cases, remains of concern. 

 In summary, both the overall and serious adverse event reporting rates are within the 

average ranges for the VAERS system as a whole. Most reported events are non-serious and 

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41

represent local and systemic reactions, consistent with the pre-licensure safety monitoring. 

Potentially preventable events, specifically post-vaccination syncope and vaccine 

administration errors, have been detected for Menactra, as they have been for other newly 

licensed adolescent vaccines. The small increased risk for GBS following Menactra in the 15- 

to 19-year-old age group persists across several analyses, but these findings do not represent a 

definitive study. Among the other serious adverse events reported following Menactra, both 

neurological and non-neurological diagnoses have been reported in relatively small numbers. 

Because of the inherent limitations of VAERS, the causal relationship of any individual event 

of vaccination is uncertain. 

 

Discussion

 Dr. Lett asked whether sanofi pasteur had plans for more manufacturing capacity, 

since there would be an increased number of doses available in 2008 due to accumulated 

inventory. Mr. Hosbach replied that the company was continuing to expand and increase 

efficiency in the existing facility, while the new facility would be brought online over time. 

 Dr. Morse noted that there appeared to be sufficient supply to cover the year, but that 

the peak occurs in July and August, just before college begins. He asked if there would be a 

surge then and whether there was enough in the pipeline to meet that increased demand. Mr. 

Hosbach replied that the company had been carrying somewhere between 1 and 2 million 

doses in inventory, which could comfortably handle any summertime surge. 

Dr. Allos reminded everyone that the most common trigger of Guillain-Barré is 

Campylobacter infection and that those infections are frequently asymptomatic and almost 

always undiagnosed. The surge in demand for the vaccine occurs at the same time that there is 

a natural peaking in the incidence of Campylobacter infection. Of the 19 reported cases of 

Guillain-Barré, almost all occurred during that time. When intensive surveillance was done 

for Guillain-Barré among children vaccinated between January and April, there were no 

cases. The data suggest that there is no relationship between this vaccine and Guillain-Barré, 

but that Campylobacter-associated Guillain-Barré happens to mirror the timing of when this 

vaccination is used. Dr. Iskander responded that there is not a great deal of testing for 

etiologic agents, so broader epidemiologic links of these cases to known outbreaks or known 

peaks of Campylobacter have not been found. This does not mean there is no possibility of 

links. CISA is in fact looking at algorithms to promote more standard evaluation of GBS, 

seeking etiologic agents. 

Dr. Keyserling noted that, given the anticipated approval for the 2-to-10-year 

indication by the end of this year, there could be a significant shortfall if there is uptake in that 

new age group. Dr. Baker responded that the ACIP does not consider vaccines that are not 

approved but the 2-to-10 group is at lower risk than the 11- to 19-year-olds. 

 Dr. Lieu pointed out that there can be a lot of confounding in the rate ratio of 2.5 

among 15- to 19-year-olds, but it remains significant after controlling for seasonality. Dr. 

Baker noted that a significant proportion of the cases had received other vaccines at the same 

time as Menactra. 

Presentation of New Recommendations 

Dr. Cohn stated that the meningococcal working group proposed recommending 

MCV4 for all persons 11 to 18 years old. A change to the MCV4 recommendation would be 

published as an MMWR notice to readers, which would have four sections: a review of the 

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May 2005 MCV4 recommendation, the revised MCV4 recommendation, a discussion on the 

implementation of the revised recommendation, and a recommendation addressing persons 

with a history of GBS. 

 The current ACIP recommendation for MCV4 includes routine vaccination of persons 

aged 11 to 12 years; adolescents at high-school entry; and other persons at increased risk of 

meningococcal disease, including college freshmen living in dorms. Recommending routine 

vaccination of 11- to 12-year-olds emphasizes the ACIP-recommended routine healthcare 

visit for 11- to 12-year-olds. Vaccination at high-school entry was intended to target an 

additional cohort of adolescents, as risk of disease increases later in adolescence, but 

implementation of adolescent recommendations for MCV4 might be affected by short-term 

supply limitations. 

 The following explains the rationale for changing the MCV4 recommendation at this 

time: "Simplified recommendations for use of MCV4 could improve coverage, and current 

and future MCV4 supply is expected to be sufficient to meet increased vaccine uptake 

resulting from simplified recommendations.” 

 The revised ACIP MCV4 recommendation would be as follows: "ACIP recommends 

vaccination with one dose of MCV4 of all 11- to 18-year-olds. Persons 11 to 12 years old 

should be routinely vaccinated at the ACIP-recommended 11- to 12-year-old healthcare 

visit." Routine vaccination is also recommended for persons who are at increased risk for 

meningococcal disease, including college freshmen living in dorms. 

The implementation section of the notice to readers will address the following issues 

related to improving uptake of MCV4: emphasis on the 11- to 12-year-old recommended 

healthcare visit; implementation of the recommendation for college freshmen living in dorms; 

and timing of vaccination, including trying to get adolescents vaccinated throughout the year 

instead of just during the summer months. The following wording emphasizes the importance 

of establishing the 11- to 12-year implementation visit. "ACIP and partner organizations, 

including the American Academy of Pediatrics, American Academy of Family Physicians, 

American Medical Association, and the Society for Adolescent Medicine recommend a 

healthcare visit for 11- and 12-year-olds to receive appropriate immunizations and other 

evidence-based preventive services. 

 "A recommendation for MCV4 vaccination among persons 11 to 12 years old could 

strengthen the role of this preventive-care visit and have a positive effect on vaccine coverage 

of all recommended adolescent vaccines.” 

To address vaccination of college freshmen, “College freshmen living in dormitories 

are at increased risk of meningococcal disease and should be vaccinated with MCV4 before 

college entry, if not previously. Because of these ability restraints in targeting freshmen in 

dormitories, colleges may elect to target their vaccination campaigns to all matriculating 

freshmen." 

The following section encourages providers to vaccinate at any healthcare visit 

throughout the year. “Because the incidence of meningococcal disease increases during 

adolescence, healthcare providers should take the opportunity to vaccinate previously 

unvaccinated 11- to 18-year-olds with MCV4 at the earliest possible healthcare visit. ACIP 

encourages healthcare providers to vaccinate with MCV4 throughout the year to minimize 

seasonal increases in demand associated with back-to-school months. Providers may want to 

consider that VFC eligibility lapses after 18 years old when making decisions about 

vaccination.” 

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 A draft notice to readers addresses CDC guidance for persons with a history of GBS. 

“Because of the reported association of Guillain-Barré syndrome after receipt of MCV4, 

persons with a history of GBS may be at increased risk and should discuss the risk of 

meningococcal disease with their healthcare provider when deciding whether or not to be 

vaccinated.” 

 This change to the MCV4 recommendation would parallel Tdap and HPV 

recommendations in the proposed 2008 adolescent immunization schedule. The language in 

the current MCV4-VFC resolution covers qualified adolescents 11 to 18 years old and would 

not need to be changed. In conclusion, the meningococcal ACIP working group anticipates 

that these recommendations would simplify provider decisions to vaccinate and improve 

adolescent coverage with meningococcal conjugate vaccine. 

Discussion

Dr. Hull referred to information from Dr. Ortega-Sanchez about uptake over three to 

five years, which would blunt the herd immunity as well as the individual protection 

provided, and wondered what effect that would have on cost-effectiveness estimates. Dr. 

Schuchat commented that herd immunity does not necessarily require a mass-vaccination 

campaign. There are many unknowns with meningococcal conjugate quadrivalent vaccine 

because nobody has evaluated herd immunity yet. However, there was tremendous herd 

immunity with the pneumococcal conjugate vaccine in infants, without an effective effort at 

catch-up. The same was true for the Hib vaccine. So using the healthcare visits to vaccinate 

anybody in that age group, one could realistically expect some herd immunity with this 

opportunistic vaccination. Dr. Ortega-Sanchez responded that the analysis was based on 

using a comparator in the no-vaccination scenario. Some vaccination is already happening, 

but there many places where the uptake has been very slow. He was not sure whether 

changing the baseline scenario of no vaccination to some vaccination would change the cost 

per life-year saved or reduce cost-effectiveness numbers. 

Dr. Lett asked whether the recommendation referred to a mass-vaccination campaign 

or routine catch-up over a period of years. Dr. Abramson replied that it was catching up. Dr. 

Cohn added that it was about opportunistic vaccination as soon as possible. 

 Dr. Lieu supported the proposed recommendation because the economic analysis and 

the Guillain-Barré syndrome analysis make clear that it would be better to deliver this 

vaccination at the 11- to 12-year-old age range or earlier in adolescence rather than later. On 

the basis of consistency and common sense, providers would clearly vaccinate a 17-year-old 

about to enter college, even though it is less cost effective. 

 Dr. Neuzil asked whether there was any evidence or biological plausibility to say 

someone who has had GBS would be more at risk for it from a different antigen. Dr. Allos 

did not believe there was any biological basis, but noted that there has been a statement about 

Guillain-Barré in all the new vaccines. Dr. Iskander added that in the vast majority of all 

cases, specific etiology is unknown, but once someone has had it, subsequent risk is increased 

globally. It is important to avoid or disentangle coincidental cases. One of the initial five 

sentinel cases was someone who had a third post-vaccination recurrent case with a common 

antigen. Dr. Abramson reminded everyone that people with a previous episode of GuillainBarré were advised not to get an influenza vaccination. 

 Dr. Gilsdorf felt there had to be a balance between the fact that the magnitude of GBS 

goes up with use of the vaccine and the fact that the disease is quite rare. Dr. Abramson 

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44

added that the incidence of GBS goes up in the 15-17 age group. 

Dr. Schuchat recalled that at the February meeting there was a decision analysis that 

looked at a ten-year framework in terms of estimated prevention of cases and deaths caused 

by meningococcal disease, as well as episodes and possibly deaths from Guillain-Barré 

syndrome, and the numbers were very much skewed towards the benefits of vaccination. 

 Dr. Pickering pointed out that death due to mening is clearly worse than GuillainBarré, but the long-term effects in adults with CNS problems from Guillain-Barré are quite 

significant. He asked whether the ISO had any plans to utilize CISA units to look at longterm CNS problems or even the genomics of this disease in the people who develop it. Dr. 

Iskander responded that there were several research protocols moving forward. The idea is to 

look at rare but instructive issues, such as recurrent GBS or recurrent post-vaccination GBS. 

The ISO also sponsors some animal model studies to get to underlying pathophysiologic 

mechanisms. Some of the most compelling cases in the literature suggest an underlying 

genetic or host-factor basis. The CISA network has identified this clinical entity as a priority. 

 Dr. Baker noted that if one included the entire 11- to 18-year-old cohort, the risk of 

invasive meningococcal disease was 0 .5; in college freshmen living in dormitories, it was 3 

to 4 per 100,000, with a conservative 10 percent death rate and another 20 percent with longterm sequelae. She thought the increased risk of Guillain-Barré in MCV4 recipients was a 

little more than one per million. Dr. Iskander agreed but pointed out that this was not the 

analysis from which one would want to extrapolate attributable risk or etiologic fraction. 

Depending on when the analysis is done seasonally, it is between one to three attributable 

cases per million doses. 

 Dr. Baker asked about the outcomes of reported cases in adolescence. Dr. Iskander 

replied that there had been no deaths and one or two individuals may still be undergoing 

rehabilitation. The more difficult question is the one of long-term sequelae and neurologic 

conditions in general. 

Dr. Turner, American College Health., recalled that for every million doses of 

Menactra administered, it was predicted that about 60 cases would be prevented among 17- 

and 18-year-olds, with 1.25 additional cases of GBS. So the risks must be weighed against 

the benefits. 

 Dr. Treanor felt the recommendation made good sense, but since children make 

relatively few visits after the 11- to 12-year-old visit, he wondered what the practical 

consequences of giving vaccines as the opportunity presented itself would be in terms of 

vaccination rates. Dr. Middleman from the Society of Adolescent Medicine reported that 

about 34 percent of adolescents make a preventive-healthcare visit, but 80 and 90 percent can 

identify a primary healthcare provider and about 70 to 80 percent have some contact with 

either an ED or a physician for another reason. So there are multiple missed opportunities. 

She added that from a practical perspective, the new recommendation makes it simpler to 

protect more adolescents. Dr. Temte from the AAFP noted that data for Wisconsin show no 

difference between the number of visits for children zero to ten and the number for those ages 

10 to 20. However most of the zero-to-ten visits are preventive, whereas the others are 

episodic acute-care visits. Ms. Stinchfield added that most clinicians were already giving the 

vaccine because they fear the disease so much. Dr. Baker emphasized the need for more 

education to expand opportunities. 

 Dr. Abramson asked whether the preference for simultaneous administration of Tdap 

and meningococcal vaccine needed to be repeated. Dr. Messonnier said that could be added 

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to the notice to readers. 

Vote

 Dr. Baker moved that the committee approve the recommendations as reviewed. Dr. 

Allos seconded the motion. 

 Dr. Allos: yes. 

Dr. Baker: yes. 

 Mr. Beck: yes. 

Dr. Gilsdorf: yes. 

 Dr. Hull: yes. 

Dr. Lett : no. 

Dr. Lieu : yes. 

Dr. Morita: yes. 

 Dr. Neuzil: yes. 

 Ms. Stinchfield: yes. 

 Dr. Treanor: abstain. 

 Dr. Morse: yes. 

 Dr. Abramson: yes. 

Dr. Lett stated that it seemed a little premature to change the recommendation. 

Providers have been confused and changing so quickly may be disruptive. She felt it would be 

better to wait another season. 

PROPOSED APPROACH TO ECONOMIC ANALYSIS OF VACCINES AND 

IMMUNIZATION STRATEGIES UNDER CONSIDERATION BY THE ACIP

Dr. Tracy Lieu, ACIP

Dr. Mark Messonnier, CDC, NCIRD/ISD

Dr. Martin Meltzer, CDC/NCIRD/OD

Dr. Lieu explained that ACIP's charter recommends that committee deliberations 

should include consideration of population-based studies, such as efficacy, cost-benefit, and 

risk-benefit analysis. Since October 2004, there have been economic presentations on 

meningococcal vaccine, pertussis for adolescents, adults and healthcare workers, Varicella's 

second dose, Hepatitis A, HPV, rotavirus, zoster, and rabies post-exposure prophylaxis. 

These cost-effectiveness studies typically use decision-analysis or computerized models, and 

are based on assumptions about vaccine effectiveness, disease epidemiology, vaccine cost, 

and duration of immunity. Those assumptions are not based on empirical studies, so 

economic analyses are particularly easy to bias. They are also hard to understand because 

there are so many numbers and each presenter uses a slightly different format to present the 

data. Therefore, the ACIP formed a working group to look at standardization of methods used 

to offer information to the committee. Recommendations were drafted based on existing 

standards set up by the U.S. Preventive Health Service. The gist of those recommendations is 

that every economic study should be carefully reviewed by CDC economists before being 

presented to ACIP or its working groups in order to ensure that the best information available 

is given to the committee or working groups as decisions are being made. 

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Dr. Messonnier talked about what needed to be included in a study and how it should 

be presented. Around 11 years ago, the British Medical Journal, developed a checklist for 

editors and reviewers to judge whether a submitted study was sufficient for publication. 

Vaccine followed suit. Many professional economic organizations require papers to be 

submitted in advance of their annual meetings as well. The working group has been working 

on a set of standards, which is almost complete. Basically they require submission of a 

manuscript comparable to a journal article, with less detail on introduction and discussion, 

and more detail on methods and results. There will be no word limit so as to get the fullest 

explanation possible. A set of presentation slides will also be required in advance. A 

suggested template is available, though not required. 

 The material should be submitted to the working group chair and a CDC liaison eight 

weeks before the general meeting in order to find a reviewer. This includes internal CDC 

studies as well. Extraordinary exceptions will be allowed, but not failure to plan. 

 There will be an internal anonymous peer review, coordinated by the NCIRD's lead 

economist. That reviewer can consult with subject-matter experts at CDC, but the completed 

review should be back to the working group chair and the CDC liaison at least four weeks 

before the general meeting to allow time for discussion, review, revision and a decision about 

whether to present it. The author must provide affiliations and statements about potential 

conflicts of interest.

 Details on methods are contained in the text document, but there are a few main 

points. First the study question must be clearly and adequately stated and the perspective 

must be societal because this is a public policy decision-making body. Other perspectives--

payer, healthcare system, patient -- are invited but not essential. 

The intervention strategies must be clearly specified and described, as well as the time 

frame and analytic horizon, and the type of economic modeling done, whether it is cost utility, 

cost-effectiveness, or cost-benefit analysis. 

 Technical equations can be included, but preferably in a technical appendix. The 

equations and the economic model should be written out in sentence form. The health 

outcomes need to be specified, along with any underlying epidemiologic models. The inputs 

used and cost values must be stated, whether they are assumed or measured, together with any 

citations from the literature or justifications for those assumptions. 

 The discount rate used needs to be specified and applied to costs and outcomes. 

Discounting has nothing to do with inflation, rather with observations made of people's 

preference for consumption over time. Undiscounted-form results can also be presented, but 

the discounting needs to be applied to all the costs and outcomes. 

There must be a multivariate sensitivity analysis, since changing one variable is 

unlikely to leave all other variables completely unchanged. Sensitivity analyses need to be 

presented in a clearly defined section with all the relevant tables and graphs, identifying the 

most influential variables. Independent replication is very important—not exact numbers but 

somewhere in the ballpark. 

 The results section of the manuscript has to answer the study question. Results must 

be clearly identified and in one place. Summary measures have to be clearly presented and 

match the perspective. Supplementary results may be presented, preferably in some sort of 

technical appendix. 

 Tables and graphs should stand alone. They should add value to the manuscript and 

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47

not detract from it. Supplementary tables can be included in an appendix as well. (Tufte is a 

good source on the guidelines for presentation of graphical data.)

 Discussion should be limited to study limitations, the study's relation to other relevant 

studies, or how the results might change if some assumptions change. Policy implications are 

not necessary since it is the ACIP's prerogative to think about the policy implications of the 

decisions it is about to make. 

 

Discussion 

Dr. Decker of sanofi pasteur said he felt the guidelines were reasonable, but was 

concerned about meeting ACIP and working group deadlines. Economic societies do require 

manuscripts, as mentioned, but they are less concerned about getting studies published 

rapidly. Some of the data may not be available to make a decision about costs and benefits if 

there was not enough time to get a manuscript written. Dr. Pickering clarified that what was 

needed was a descriptive paper that will allow CDC economists to say this is a scientifically 

valid study and be understood by non-economists 

 Dr. Decker than asked what would happen if, for example, something was about to be 

licensed and there was an economist who was able to brief the committee but had not written 

anything. Dr. Schuchat responded that the ACIP is a volunteer, deliberative body that is 

making important decisions for the country, including inclusion of vaccines in the Vaccines 

for Children program, which has a huge economic impact. This committee is asked to 

understand, digest, deliberate and vote based on cost-effectiveness data. She felt it was 

reasonable to expect members to receive complete, well-documented data, with adequate time 

for an independent economist to review and weigh in on them. The working group is just 

requesting a complete, interpretable analysis, with documented methods and assumptions, and 

results in a standard format. 

 Mr. Beck commented that when he joined ACIP, he was absolutely amazed at the 

quality of the economic data presented. It would never have been permitted in the corporate 

world. He felt there needed to be a system and a level playing field, and welcomed the new 

guidelines. 

Dr. Treanor noted that listening to presentations that he could not understand was 

actually counterproductive in terms of making a decision. Dr. Feinberg agreed that it was in 

everyone's best interest to make sure the data used to make recommendations were as 

outstanding, rigorous, and thoroughly vetted as possible. He wondered whether any thought 

had been given to seeking external reviewers and what would happen if there was a difference 

of opinion between reviewers. Dr. Pickering responded that the CDC planned to put together 

a list of CDC economists as well as outside reviewers who could be contacted for special 

expertise. There also needs to be a time line, since implementation of the new guidelines will 

be gradual. Regarding Dr. Feinberg’s second question, Dr. Messonnier responded that 

criticisms had to be valid and reasonable before there would be rejection of a manuscript. A 

provision will be made for comments from the reviewing economist to be aired as well. 

 Dr. Markson from Merck asked how the committee would handle multiple models, 

developed by several groups. Dr. Messonnier replied that it would be up to the working 

group to decide whether to hear two or three different estimations on cost-effectiveness or 

cost benefits. 

VACCINE SUPPLY AND IMPLEMENTATION

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Dr. Greg Wallace, CDC/NCIRD/ISD

Dr. Wallace first gave the committee a brief update on varicella zoster virus bulkbased vaccines, which include varicella vaccine (Varivax); MMRV(ProQuad); and the zoster 

vaccine (Zostavax). When Merck temporarily suspended production to work out yield issues, 

the ad-hoc supply work group recommended no change in the varicella vaccine vaccination 

policy, which meant the two-dose schedule should still be implemented. Merck was 

prioritizing production of Varivax and Zostavax and expected MMRV (ProQuad) to be 

depleted in the third or fourth quarter of 2007. After announcing the production issues, Merck 

experienced record sales of ProQuad, and supply was exhausted by June 15th. Any current 

orders through the CDC contract may not be filled until July or August. However, there is no 

change in the recommendation for vaccination to protect against varicella disease; Varivax 

supply is adequate to meet these needs and Varivax and MMR would be given as separate 

doses. Mixing the two together to try and make ProQuad will not work. 

Dr. Wallace then reviewed implementation of adolescent vaccines, particularly in the 

public sector. Overall, the CDC contract accounts for around 50 percent of the national total 

for pediatric and adolescent vaccines. 

 Regarding public sector demand, CDC started off with around 46 percent of the 

Menactra market in 2005. This dropped to 40% in 2006, but there was a modest increase in 

the number of doses purchased. Through the first half of 2007, no increase has been seen, but 

decisions made earlier in the meeting may have some impact. Tdap started slowly (24% of 

market in 2005), but the contract happened relatively late in the season and probably missed 

some of the pre-school vaccination in the public sector the first year. The market share 

increased to 41% in the second year of implementation, but appears to have dropped off in the 

first half of 2007. The CDC contract was two months after the licensure for HPV in 2006, but 

caught up pretty quickly and has increased the number of doses purchased. 

Another way to look at adolescent implementation status is as follows: CDC 

purchased approximately two cohorts worth of Tdap vaccine in 2006, but that appears to be 

falling off in 2007. For HPV, about one cohort of a three-dose series has been purchased to 

date and CDC is a bigger proportion of that market than for other adolescent vaccines. For 

Menactra, grantees purchased doses for less than half of a cohort for each of the last two and a 

half years, so there is certainly room for improvement there. 

 With the CDC contracts and new vaccines, there tends to be a lot of enthusiasm for the 

vaccine early on, but reaching adolescents is still a big challenge. The adolescent platform is 

not the same as the pediatric; the 11- and 12-year-old visit does not have the same coverage as 

the four- to six-year-old visit and may involve different providers. Also, activity in the 

adolescent arena tends to be disease specific. Grantees have gotten some pushback by groups 

with specific vested interests instead of looking at the big picture. New access strategies need 

to be developed and grantees need guidance from others who have learned what works. 

Discussion

 Dr. Stanley Plotkin asked whether any thought had been given to repairing the schoolbased immunization system. Dr. Schuchat announced that there would be a supplement to 

Pediatrics focusing on adolescent immunization, which will pull together results from a 

workshop about a year and half ago. It is an area of major importance to CDC and many of 

the liaison groups, and will require a lot of creativity. School-based immunization has been 

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49

successful in many areas and allows for quite a bit of public/private collaboration. She also 

mentioned the September workshop on school-aged recommendations for influenza, which 

will include thought about the school venue. Dr. Abramson added that NVAC also had an 

adolescent work group thinking about this issue. 

UPDATE: PNEUMOCOCCAL WORKING GROUP

Dr. Julie Morita, ACIP Working Group Chair 

Dr. Morita explained that the working group’s charge was to review the need and 

optimal timing for updated statements on the use of the conjugate vaccine and the 

polysaccharide vaccines and to develop a revised statement on the use of the pneumococcal 

vaccines for ACIP review and for approval. The polysaccharide vaccine statement was issued 

in 1997 and the conjugate vaccine recommendations were issued in 2000. The group’s 

agenda included any changes to the current recommendations based on existing data, for 

example, direct and indirect population effects from the conjugate vaccine, non-vaccine 

serotype replacement, or trends in antimicrobial resistance. In addition, the group reviewed 

the conjugate use and effects in special populations, specifically Alaskan-native and 

American-Indian children, and alternative vaccine schedules with reduced number of vaccine 

doses. 

 A number of presentations were made to the working group. Matt Moore described 

trends in invasive pneumococcal disease in the U.S. before and after the conjugate vaccine. 

Marie Griffin from Vanderbilt reviewed the population impact of the conjugate vaccine on 

pneumonia, hospitalizations, and otitis media visits. Tom Hennessy and Ros Singleton from 

Arctic Investigations Program reviewed an increase in invasive pneumococcal disease in 

Alaskan-native children due to serotypes not in the conjugate vaccine and Kate O'Brien 

reviewed the impact of nine years of conjugate vaccine use on invasive pneumococcal disease 

among Navajo children. Wyeth Vaccines reviewed the comparative immunogenicity of 

conjugate vaccine using a two-plus-one alternative dosing schedule. Tammy Pilishvili from 

CDC also reviewed the post-licensure effectiveness of conjugate vaccine against invasive 

pneumococcal disease in the U.S. Pekka Nuorti reviewed the uptake of conjugate vaccine 

among children in the United States, and David Goldblatt reviewed the experience with 

reduced conjugate dose schedules in the U.K. Lastly, Philippe DeWals from Canada 

reviewed the impact of the three-dose conjugate vaccine program in the province of Québec. 

 Key issues regarding the pneumococcal polysaccharide vaccine include contradictory 

data regarding vaccine effectiveness, and limitations of the polysaccharide vaccine in elderly 

persons and high-risk groups. It will also review the duration of protection, safety, and 

immunogenicity of revaccination and optimal timing and frequency of revaccination. The 

goal is to look at the overall achievable public health impact. 

 Lisa Jackson reviewed contemporary studies of the polysaccharide vaccine efficacy 

and effectiveness. Outcomes included invasive disease, pneumonia, and mortality. Those 

study designs included clinical trials, observational studies, and ecological studies. 

Considerations regarding revaccination with polysaccharide vaccine include the duration of 

protection, safety, immunogenicity, and effectiveness of first revaccination; safety of multiple 

revaccinations; and the optimal timing and frequency of revaccination. 

 Before the October meeting, the group hopes to look at possible new polysaccharide 

target groups based on available data regarding newly identified risk groups; the 

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50

polysaccharide programmatic and implementation issues; some updated polysaccharide and 

conjugate economic studies; and the manufacturer's review of potential time lines for new 

pneumococcal vaccines in the pipeline. 

 

Discussion

 Dr. Abramson asked whether the workgroup would look at the use of a combination of 

PCV7 and pneumococcal 23 in the same patient, for example a sickle-cell patient. Dr. 

Whitney responded that the group still needed to go over all those high-risk groups and new 

data that may have become available since the last recommendation. 

 Dr. Bruce Gellin noted that there needed to be more clarity about the use of 

pneumococcal vaccine as part of pandemic preparedness. Advice from the committee would 

be welcomed regarding whether people should be vaccinated now, should there be a stockpile, 

is there a role for conjugate vaccine, etc. Dr. Morita replied that this issue was in the original 

work plan. 

UPDATE FROM THE PREGNANCY AND BREAST-FEEDING WORK GROUP 

Dr. Kathy Neuzil, ACIP WG Chair

Dr. Stephanie Schrag and Dr. Tami Skoff, CDC, NCIRD/DBD

Dr. Neuzil introduced the new ACIP working group on vaccines during pregnancy 

and breast-feeding. The main motivation behind forming this working group was the 

recognition that pregnant women and newborns are at risk for vaccine-preventable diseases, 

and yet attention toward vaccine coverage in these groups and vaccine recommendations in 

these groups is not always optimal. Recent discussions around new vaccines like HPV and 

Tdap highlighted these issues. For HPV, during the catch-up period women up to age 26 will 

be vaccinated; for Tdap there has been concern about harmonization with other professional 

societies for pregnancy-specific recommendations. 

Dr. Schrag explained that the new working group initially spent time thinking about 

terms of reference and identified three main tasks. The first was to review existing 

recommendations for use of vaccines during pregnancy and breast-feeding. The second will 

be to develop guiding principles to inform development of ACIP recommendations for 

pregnant and breast-feeding women as new vaccines are licensed and existing 

recommendations are routinely updated. Finally, the group wants to help resolve 

inconsistencies within ACIP recommendations and facilitate harmonization of ACIP 

recommendations with those of other professional organizations. 

 In addition to three ACIP voting members, the working group has liaison 

representatives from AAFP, ACOG, and AAP, as well as from FDA and the NIH group in 

charge of maternal vaccine research. There are also many subject-matter experts representing 

current vaccines indicated for adolescents or adults and relevant subject areas, for example, 

immunology and health law. 

 The work-group membership was identified in January and the first in-person meeting 

was held in February at the last ACIP meeting, where it focused mainly on terms of reference. 

Since then, the focus has been on reviewing existing recommendations by conference call. 

Dr. Skoff briefly summarized some of the general themes uncovered thus far. The 

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ACIP stated in an MMWR that the risk to a developing fetus from vaccination of the mother 

during pregnancy is primarily theoretical, based on the fact that, to date, no evidence exists to 

support a risk from vaccinating pregnant women with inactivated virus, bacterial vaccines, or 

toxoids. That MMWR also stated that the benefits of vaccinating pregnant women usually 

outweigh potential risks, when the likelihood of disease exposure is high, when infection 

would pose a risk to the mother or fetus, and when vaccine is unlikely to cause harm. 

As a starting point, the working group tried to categorize existing ACIP 

recommendations and found variation both in the recommendations themselves and the 

language of the recommendations. But it did come up with four general groupings of 

vaccines. The first group is recommended for all pregnant women; to date, the only vaccine 

that falls in this category is inactivated influenza vaccine. The second is those vaccines that 

follow routine adult immunization recommendations regardless of a woman's pregnancy 

status. The third and largest group is vaccines recommended for pregnant women only under 

special circumstances, such as when exposure risk is high, and the last group includes 

vaccines that are not recommended for pregnant women. 

Many of the ACIP recommendations are challenging to interpret. In fact, it is not 

uncommon for similar recommendations to use very different language. Second, there seems 

to be an inconsistent message about the role of limited safety and/or efficacy data for some of 

these vaccines. For some products, limited data are used to support vaccination of pregnant 

women, whereas for others, lack of sufficient data is a reason against vaccination. When 

grouping the vaccines based on their recommendations, it was found that the majority of the 

vaccines are recommended for pregnant women when the benefits of vaccination outweigh 

the risks to the individual. This type of language places a large burden on healthcare 

providers and pregnant women to make responsible decisions about vaccination during 

pregnancy. Finally, the ACIP does address the issue of breast-feeding and makes an overall 

general statement supporting vaccination in breast-feeding women, the notable exception 

being smallpox vaccine. 

 The second work-group call focused on a review of the FDA process for making 

indications for the use of vaccines during pregnancy and breast-feeding. As part of that 

process, all vaccines must be classified under one of five pregnancy categories, which are 

based on the risk of reproductive and developmental adverse effects and, for certain 

categories, on the basis of such risk weighed against potential benefit. Of the currently 

licensed vaccines, all but two fall under Category C, which includes products that lack human 

data, but for which animal studies have shown an adverse effect on the fetus or animal studies 

have not been done. 

These pregnancy categories are often confusing because they convey the false 

impression that there is a gradation of risk among categories and the same level of risk within 

any given category. The FDA is improving pregnancy labeling and considering either 

changing or creating alternatives to the current pregnancy categories. 

The group discussed the fact that vaccine companies write the vaccine labeling and 

that it is the responsibility of the FDA to review and approve the label language. The content 

is constrained by federal regulations. No implied claims of product use may be made if there 

is inadequate evidence of safety or lack of product effectiveness, which limits what can be 

printed on the labeling. In general, the language on the labeling tends to be much more 

conservative than the language of the ACIP recommendations, not only for vaccination during 

pregnancy, but also during breast-feeding. 

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52

 The most recent conference call focused on the recommendations of AAFP, ACOG, 

and AAP, which are generally harmonized with ACIP's recommendations, although 

interpretation may vary. Translation of the recommendations by the organizations to a more 

user-friendly and easy-to-understand language can be challenging and may actually result in 

altered content of the original recommendations. The biggest difference in recommendations 

was observed for Tdap, which is recommended for pregnant women by AAP and is under 

consideration for a similar recommendation by ACOG. 

 The next step is to start discussions on the development of guiding principles for 

recommendations for vaccines during pregnancy and breast-feeding. 

Discussion

Dr. Schaffner expressed surprise that Td did not fit into the universal pregnancy 

immunization category. It was his impression that before the ACIP made its recommendation 

regarding influenza vaccine, the vaccine was universally recommended. Dr. Neuzil 

responded that this confusion was related to inconsistencies in the way recommendations 

were worded. Td is recommended for pregnant women if they are unvaccinated, or due for a 

booster. Dr. Houn of the FDA added that Category C actually has two meanings, which is 

confusing. One is that there is an absence of animal data as well as an absence of human data, 

which is probably the case for Td. The second is that the animal data show adverse effects 

but there is absent human data. 

Dr. Baker clarified that the FDA was consistent about Td, so it belongs in Category C, 

as does influenza. Both are recommended on the basis of public health issues. HPV did pass 

into Category B. To obtain category B, the vaccine manufacturers must request that category 

and then provide the data, and the minimal data are animal data. She felt the FDA rules were 

very straightforward and that the disconcerting thing was that Category B is considered okay 

and D is bad. 

 Dr. Iskander suggested that the work group could also provide clarity and education 

on pregnancy registries, why they exist and what lessons have been learned from them. It 

might even be possible to frame some recommendations about preferential reporting to 

registries rather than to other passive surveillance systems. Dr. Whitley-Williams noted that 

the Department of Defense has a wonderful registry, which showed that some pregnant 

women were inadvertently immunized. Some of the data on congenital rubella syndrome also 

come from that database. 

 Dr. Peter noted that there was a lot of research going on regarding immunizing 

pregnant women to protect the newborn, which should give the working group considerable 

work in the future. Dr. Neuzil added that the group was looking at burden of illness both in 

the pregnant women and in the newborn. 

 Dr. Plotkin emphasized that if the group could come up with general conclusions, it 

would be very helpful in trying to convince manufacturers to develop vaccines that would be 

used in pregnancy and would provide some protection in legal matters. He also commented 

that assessing the risk of disease in the pregnant woman was inherently difficult, and favored 

taking that aspect out. For example, risk is a very difficult way of evaluating whether to give 

a vaccine to a woman who is traveling. 

 

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Day Two June 28, 2007 

INFLUENZA VACCINES

Dr. Ban Mishu Allos, WG Chair 

Dr. Anthony Fiore, CDC/NCIRD/ID

Dr. Angela Calugar, CDC/NCIRD, ISD

Dr. Karen Broder, CDC/ISO

Dr. Gina Mootrey, CDC/NCIRD/ISD

 

 Dr. Fiore thanked the departing influenza work-group members who are also members 

of the ACIP and noted that during their tenure vaccination was expanded to include children 

aged 23 to 59 months old and their household contacts, and a framework and a time line were 

laid out for expanding the recommendations to additional ages and groups. 

 

Influenza Activity in the US during 2006-2007 

Dr. Fiore presented data from laboratory surveillance conducted by the U.S., the 

World Health Organization and the National Respiratory and Enteric Virus Surveillance 

System through June 5th, 2007. Since October 1st, about 173,000 specimens have been tested 

for flu viruses, of which 13 percent were positive. Among the 22,000 positives, 79 percent 

were influenza A and 21 percent were influenza B. About a third of the influenza A viruses 

have been subtyped: 64 percent were influenza A-H1 viruses and the rest were H3 viruses. 

The season peaked in mid to late February. The intensity and peak time were similar to the 

previous two seasons. Deaths attributed to pneumonia and influenza did not exceed the 

epidemic threshold during the season, based on information from the 122-city mortality 

reporting system. 

Laboratory-confirmed influenza-associated pediatric hospitalization is tracked in 

several population-based surveillance networks. Rates for this past season were similar to the 

rates of the past two seasons, for children aged 4 and under and for children 5-17 years old, 

and were considerably below the rates observed during the 2003-2004 season. As of June 

22nd, CDC had received 67 reports of influenza-associated pediatric deaths this season, 

compared to 45 and 46 deaths, respectively, in the last two seasons, and about 153 in the 

2003-2004 season when reporting began. 

 Compared to the previous two seasons, there has been an increase in the mean age of 

reported influenza deaths to seven years from four to five years in 2004 to 2006. There has 

also been an increase in the proportion reported to have the invasive MRSA-associated coinfections along with influenza, from less than 5 percent in the previous two years to 27 

percent this past year. CDC and the state health departments are planning additional 

investigations and increased surveillance for these MRSA-influenza co-infections among 

children. 

Dr. Fiore shifted attention to the time frame for considering expansion of the 

recommendations, which may include school-aged children by 2008, followed by household 

contacts and caregivers of those school-aged children and then, by 2012-2013, discussion of 

implementation of universal vaccination for all age groups. Expanding the recommendations 

to include routine vaccination of school-aged children has been a major topic in the workgroup discussions over the past year. A CDC/CSTE-sponsored consultation to consider the 

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54

scientific and implementation issues raised by the proposed expansion will be held September 

10th and 11th in Atlanta. Approximately 75 consultants have been invited, including 

influenza researchers and epidemiologists, representatives from public health and professional 

and medical organizations, community vaccinators, safety experts, and people who have 

implemented vaccination programs in school-aged children. The agenda will include a review 

of the evidence base supporting expansion of the recommendations, including the burden of 

disease in this age group; vaccine effectiveness and safety; cost analyses; the potential direct 

and indirect impact in communities; and experiences and pilot projects from around the 

country and in other countries. Key evidence gaps will be identified. The second day will 

largely focus on implementation challenges and the potential solutions, which would include 

sustainability, infrastructure and resource needs, the feasibility of delivering the vaccine in 

nonmedical and medical settings, priority communication messages, and how to assess impact 

over time. The outcomes of this meeting will be presented at the October 2007 ACIP meeting. 

 Dr. Fiore briefly mentioned the strain selections for the upcoming season, which were 

made at the VRBPAC meeting and FDA on February 28th. One strain has been changed out. 

The A/Solomon Islands/3/2006 strain will represent the H1N1 antigens. The other two strains 

are the same as last season -- the A/Wisconsin/67/2005 (H3N2) and B/Malaysia/2506/2004. 

Dr. Fiore introduced a discussion of the FluMist licensure. FluMist was first licensed 

in June 2003. The frozen formulation was licensed for use in healthy persons aged 5 to 49 

years. In January 2007, a liquid formulation was licensed, which allows the product to be 

shipped and stored in a refrigerated state. Commercial use was anticipated during this 

upcoming flu season. Around the same time, MedImmune submitted a BLA application to 

FDA for use of liquid FluMist in children aged 12 to 59 months of age without a history of 

wheezing and asthma. The analyses were presented on May 16th to VRBPAC. The primary 

data source was the pivotal trial CP-111, published by Belshe, et al, in the New England

Journal of Medicine in 2007 and also presented here to ACIP, both in October 2006 and in 

February 2007, with the later presentation focusing largely on safety issues. This was a 

randomized, double-blind active control with TIV multi-center study, with pre-specified 

analyses for 6- to 23-month-olds and 24- to 59-month-olds. 

The FDA concluded that the data indicated that FluMist was safe and effective in 

subjects 24 months of age and older. However, among subjects less than 24 months of age, 

there were some safety concerns, including the fact that participants who received FluMist 

had increased all-cause hospitalizations, severity of wheezing, and severity of respiratory 

events, compared to the TIV-receiving group. FDA also noted that a history of wheezing was 

poorly predictive of wheezing post vaccination among FluMist recipients. Persons with a 

history of severe asthma were excluded, but about 20 percent of participants did have a 

history of wheezing. 

 All of the adverse events were uncommon, mostly among the children 6 to 11 months 

old. However, the FDA noted that the post hoc analyses conducted among the 6- to 11-

month-olds should be interpreted with caution, recalling that the pre-specified age-group 

analyses were for 6- to 23-month-olds and 24- to 59-month-olds. 

After hearing the evidence, the committee members concluded that FluMist efficacy 

was not inferior to TIV. For the safety vote, the committee was asked whether the data 

demonstrated that the benefits would exceed the risk of FluMist in three groups. For children 

12 to 59 months of age without a history of wheezing and asthma, the vote was nine yeses and 

six no’s. For 6- to 23-month-olds, regardless of wheezing history, the voting was three yeses 

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55

and 12 no’s, and for children 24- to 59-months, regardless of wheezing history, the vote was 

15 yeses and zero no’s. 

 The FDA decision on licensure is currently on hold pending resolution of issues 

identified during manufacturing plant inspections, but this is not expected to significantly 

affect availability of FluMist for the 2007-2008 influenza season. MedImmune can continue 

to manufacture its products while taking corrective action, however this makes it difficult to 

come to a decision on the age-indication change, so the committee vote as well as the VFC 

vote will be delayed. 

 The influenza working group members agreed that the data indicated that FluMist 

efficacy was not inferior to TIV for all the age groups in the study. In fact, FluMist provided 

significantly increased efficacy compared to TIV in the flu year studied. The data also 

indicated no safety signal among children 24 months and older with no history of wheezing. 

However, there was concern that additional information was needed, particularly for children 

6 to 11 months old, with regard to wheezing outcomes and all-cause hospitalization rates 

compared with TIV; additional information on safety was also needed for children 24 months 

of age or older with a history of asthma or wheezing. 

 The working group will review the FDA-approved age and medical indications once 

they become available. Clinicians and immunization programs must be able to screen for 

conditions that are a contraindication to LAIV use, such as a history of asthma or recurrent 

wheezing. The working group will also continue discussions on the advantages and 

disadvantages of recommending LAIV over TIV for healthy young children, based on the 

interesting but limited data showing that LAIV has better efficacy in preventing labconfirmed influenza among young children. Finally, safety monitoring will be critical, 

including updates from the Vaccine Adverse Events Reporting System, the Vaccine Safety 

Datalink, and the other planned postlicensure safety studies. 

Discussion

 Dr. Neuzil asked whether Dr. Fiore could provide an update on antiviral resistance 

from this past year and if there were any plans for a case-controlled study to get more 

definitive data on the efficacy of influenza vaccine in preventing death in children. Dr. Fiore 

responded that resistance to the adamantanes continues to be quite high: 80 percent or more 

and even 100 percent in some parts of the world. So for this coming year, CDC advises not 

using the adamantanes for treatment or chemoprophylaxis of influenza. Resistance to the 

neuraminidase inhibitors remains well below 1 percent. For the upcoming season, a health 

advisory network letter was sent out to stimulate reporting of severe illness with MRSA coinfection and not just deaths, with the hope of capturing larger numbers to expand the study 

size. CDC is looking for both influenza virus isolates and MRSA isolates, since it does not 

have MRSA isolates from the dozen or so children previously reported. From the influenzavirus testing, no particular strain appears to be associated with these co-infections. As cases 

are accumulated, an epidemiologic investigation will be carried out using population-based 

surveillance systems and then the case-control study will be resumed if an increase in these 

co-infections is identified. 

 Dr. Morse pointed out that there is a two-year gap in considerations for the flu 

vaccine and suggested that this gap could be decreased since the vaccine supply seems to be 

increasing steadily. Also, for pandemic flu preparations, it is probably better to have a larger 

vaccine supply available sooner. He wondered whether the timetable could be moved up. 

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56

Dr. Allos explained that the working group’s goal was universal protection and that it may not 

be necessary to vaccinate everybody to achieve full protection. The reason for the gap is that 

once all school children up to the age of 18 have been vaccinated, there needs to be a period 

of time when surveillance data can be collected to assess the decline in flu rates in the elderly 

populations, based on expanded vaccination. 

 Dr. Poland argued that such a study would be fine in a static population, but given the 

number of people who travel each year, questions about the real impact of the new policy 

could not be answered. He also noted that there are many adults not covered by existing 

recommendations and the number of deaths among this population was much greater than 

those among school-aged children. In addition, millions of doses of influenza vaccine are 

thrown away each year, while more manufacturers are coming into the market, so previous 

fears about supply not keeping up with demand were unfounded. Given that there is a vaccine 

informed by six decades of efficacy and safety data and annual epidemics kill tens of 

thousands of Americans, he recommended moving quickly to universal vaccination, with an 

emphasis on specific high-risk target groups. 

Dr. Baker reminded the audience that there was already a recommendation to 

immunize all children 6 to 59 months of age, but less than 20 percent of that group was 

actually getting immunized. Physicians and the general public continue to believe that the 

vaccine has to be given before November and young children have to have two doses at least 

four weeks apart. However, for the past ten years, 60 percent of the flu seasons have peaked 

in February, so vaccination needs to continue through December and even into January. 

Everyone was shocked at the Prevnar efficacy in the un-immunized older population. Young 

children have higher titers of flu, and they shed almost twice as many days as do adults. Thus 

there is good reason to a better job with pediatric immunization, followed by surveillance. 

 Dr. Baker noted that the National Foundation for Infectious Disease has a new 

initiative called the Childhood Influenza Immunization Coalition, whose goal is to protect 

children against influenza by communicating with one strong voice the importance of making 

influenza immunization a national health priority. The coalition is led by the Surgeon General 

and co-chaired by Dr. Baker. On May 23rd, over 20 of the nation's leading public health, 

medical, and parent organizations met to discuss the objectives of the coalition and outline 

ways to improve immunization rates. The coalition will educate healthcare professionals and 

parents on the importance of vaccinating children throughout the influenza season and then 

measure the outcome of their campaign. 

 Dr. Poland pointed out that with pertussis the policy is not to immunize adults to 

protect children, even though adults are a reservoir for pertussis. Because all adults cannot be 

immunized, children are immunized against pertussis. Similarly, because all children have 

not been immunized against influenza, and because of the dynamicity of the adult population, 

adults need to be immunized. However, he applauded the initiation of a new coalition that 

would push for influenza immunization. 

 Dr. Schuchat asked what kinds of studies were being done on vaccine effectiveness for 

direct protection in children. Dr. Fiore responded that vaccine efficacy studies were going on 

in several different sites, including the Marshfield group and the EIP sites, as well as in the 

new vaccine surveillance network sites. The aim is to do more rapid efficacy estimates that 

would be available shortly after the end of the season. The past couple of flu seasons have 

been very mild and the few cases that were available to study were actually the same 

circulating strains in the vaccine. Influenza epidemiology makes it difficult to design studies 

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57

that reliably have the power to measure efficacy. 

 Dr. Abramson asked whether the timetable would be part of the September meeting’s 

deliberations. Dr. Allos indicated that it would not. Dr. Schuchat pointed out that the focus 

of the September meeting would be on the first point on the timetable, based on information 

about effectiveness, safety, feasibility, and logistics. The rest of the timetable will depend on 

what happens with the first point. 

 Dr. Treanor observed that because of the extreme variability from season to season, it 

may not be possible to gather useful data over a short time period. A drop in pediatric deaths 

over a couple of years could be the result of a vaccination campaign but could also represent 

epidemiologic variability. 

 Dr. Hosbach of sanofi pasteur asked whether manufacturers would be invited to the 

September meeting. Dr. Fiore replied that vaccine supply was not considered a limiting 

factor. Dr. Hosbach noted that vaccine manufacturers were also interested in increasing 

immunization rates and that the logistics of immunization was part of their planning for each 

flu season. Dr. Lewin of the Biotechnology Industry Organization added that manufacturers 

are not just suppliers. They can also provide guidance on products that are in development 

and indications, as well as their experience in distribution and ideas that might help 

implement these recommendations smoothly. 

 Dr. Tan of the American Medical Association and also representing the National 

Influenza Vaccine Summit, advised that physician groups prefer a simpler recommendation 

for vaccination and would support moving toward universal recommendations. 

 Dr. Duchin of Seattle, Washington expressed concern about the two-year observation 

period after the recommendation to expand to all school-aged children, particularly in the 

context of looking at any effect on older adults. He felt it was a very short time frame and 

encouraged the committee to consider ways to facilitate uptake, particularly in the school 

setting. 

 Ms. Stinchfield requested that there be a phone conference if the FDA FluMist 

decision were to come through during the next few weeks. The issue is time sensitive and 

there will also have to be public notice. Dr. Abramson added that the label will probably be 

for age two and older, which makes the consideration somewhat easier, but the committee is 

getting five new members who must be caught up before there is a vote. 

Update on FluMist Safety Monitoring

Dr. Broder reminded the committee that the general approach to safety monitoring of 

new vaccines or new indications is to review prelicensure safety data to identify potential risk 

from Phase III prelicensure trials, recognizing that rare adverse events may not be apparent 

until wider use. Post marketing data are reviewed and then a Vaccine Adverse Event 

Reporting System monitoring plan is developed, as well as a Vaccine Safety Datalink project 

plan, where risk is assessed through near real-time or planned studies. Next the need to create 

key case definitions is identified, along with candidate protocols and special studies that 

might involve collaboration with other partners. 

 The main study supporting the FluMist age change under consideration was a multicenter randomized trial. About 50 percent of the subjects were in the U.S. and the age group 

was 6 to 59 months. The study group received FluMist and an intramuscular placebo saline, 

while the active control group received TIV plus an intranasal placebo of saline. Each group 

enrolled about 4,000 children. Subjects were excluded if they had a history of severe asthma 

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or medically diagnosed or treated wheezing within 42 days before enrollment, but they were 

not excluded for more mild forms of wheezing. In fact, recurrent wheezing was a criterion for 

stratification in the study. 

There were two pre-specified safety outcomes. The primary one was medically 

significant wheeze (MSW), and the secondary one was any wheeze. MSW was the presence 

of wheezing on physical exam and at least one of the following: signs of respiratory distress, 

hypoxemia, or a new prescription for a daily bronchodilator that was not prescribed on an asneeded basis. 

 The key safety finding was an increased risk for MSW in children age 6 to 23 months 

after FluMist, compared with TIV. This risk was not observed in the 24- to 59-month group. 

Although the breakdown of 6 to 11 months and 12 to 23 months was not an original prespecified age group, that risk persists when the data are analyzed that way. 

 Compared with TIV recipients, FluMist recipients had more frequent reports of runny 

nose, nasal congestion and low-grade fever after Dose 1. But they had a similar rate of 

serious adverse events (about 3 percent in both arms), which were rare throughout the study's 

six-month period. The vast majority of these SAEs were hospitalizations. FluMist recipients 

in the age group 6 to 11 months (not a pre-specified age group) did have an increased risk for 

all-cause hospitalizations during that six-month monitoring period for SAEs. In the FluMist 

group, 6.1 percent of the recipients were hospitalized versus 2.6 in the TIV group. The rates 

persisted when looking at respiratory hospitalization versus all-cause hospitalization, but no 

supporting biologic mechanism was apparent. 

 Dr. Broder then shared some data from VAERS for the current indication, which is 5 

to 49 years in persons without a history of wheezing or asthma. From licensure through the 

end of February 2007, VAERS received 744 reports after FluMist. About 6 percent of the 

reports overall were serious, and only 15 reports were received among children less than five. 

This was an off-label indication, and none had serious adverse events. When serious adverse 

events are linked to age, they are all less than 10 percent, which is lower than expected for 

VAERS reports. 

 The most common reported condition overall was respiratory events. In the pediatric 

age group, 6 percent of the reports were asthma-wheezing. Of the 16 reports, 7 had a history 

of asthma or wheeze, which indicates off-label use. This raises the question of whether it 

might be more likely to occur in a younger group where wheezing is common and screening 

might be harder. 

Three questions seem critical. First, when the screening criteria are established, 

particularly for exclusion related to wheezing, will the screening for history of wheezing 

appropriately identify children who should or should not receive vaccination? Second, is the 

safety profile of FluMist within about six weeks or possibly a little longer after vaccination 

comparable to TIV in children less than five years? It will be important to look at the risk for 

medically attended wheeze and for all-cause hospitalization, as well as potential unexpected 

safety signals. Finally, if there is some off-label use or if there is a permission for use in 

certain wheezing populations, are children with a history of wheezing in fact at increased risk 

for wheezing or hospitalization or other adverse events after FluMist compared with those 

who do not have such a history? 

VAERS will be the cornerstone of initial monitoring, particularly if uptake is low. 

CDC and FDA scientists will review daily alerts of serious adverse event reports and other 

medically important conditions, including medically important wheezing after FluMist. The 

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59

second avenue will be the Vaccine Safety Datalink. The main limitation of VSD is limited 

power to assess risk for rare adverse events, particularly if uptake is low. VSD will examine 

the clinically important outcomes in children, especially medically attended wheezing and allcause hospitalizations. But the FDA licensure and ACIP recommendation decisions and the 

uptake patterns in the VSD will affect specific aims and methods of the VSD study. 

 The Brighton Collaboration is developing standardized case definitions for wheezing 

and asthma outcomes, which will be important to communicate risk information and 

screening guidance. A primary vehicle will be the vaccine information statement. Finally, a 

Phase IV study is under way among 60,000 FluMist recipients aged 5 to 49 in the Kaiser 

Permanente system. This manufacturer-sponsored study has no CDC involvement. Results 

are anticipated in 2011. 

Discussion 

 Dr. Schaffner asked whether children with a previous history of asthma and wheezing 

had more serious cases of influenza and whether hospitalization was increased. He wondered 

whether that information was needed to contrast what is happening after either vaccine. Dr. 

Abramson replied that flu was a well-known inducer, however it is not clear that the virus has 

to get into the lung to induce asthma. Dr. Iskander commented that a corollary question was, 

what is known about the inactivated influenza vaccine and wheezing? Several VSD studies 

revealed that the initial signal of wheezing following inactivated influenza vaccine was 

ultimately found to be an artifact of low vaccine coverage and the fact that children with more 

severe asthma disease were more likely to get the vaccine in the first place. 

Dr. Whitley-Williams was concerned about the use of historical screening for asthma, 

especially in the 6- to 11-month-old age group. Wheezing is often associated with upper 

respiratory tract infections, which have viral etiology, yet parents may not be aware that the 

child has asthma reactive airway disease. 

Since asthma is significantly on the rise in some minority and urban populations, Dr. 

Whitley-Williams asked if there was any information about whether postvaccination 

wheezing occurred more in any particular group. Dr. Broder replied that VAERS does not 

routinely collect that information. Dr. Walker from MedImmune talked about CP-111, a 

multinational study in North America, Europe, and Asia, where about 80 percent of the 

children were Caucasian. In that study, there were no appreciable ethnicity differences in 

terms of asthma rates, although the Asian population was only about 5 percent. The study did 

find that rates were more common in males than females, across the board for both FluMist 

and TIV recipients. Dr. Malinoski added that MedImmune had made three post-marketing 

commitments with the FDA pending approval, one of which was a large study in children less 

than five. It will obviously be possible to collect ethnicity data within that analysis. 

MedImmune has two additional studies that will look at the effectiveness of the label in 

excluding children less than 24 months of age and excluding children and adults with asthma 

and recurrent wheezing as a surrogate for asthma. Those studies can be shared with the 

working group or members of the safety group at CDC. 

 Dr. Malinoski informed the group that the current proposed label was for children 24 

months and above, with warnings and precautions for anyone with asthma and children less 

than five with recurrent wheezing as a surrogate for asthma, so that the label consistently 

excludes anyone from 2 to 49 years of age with asthma. Discussions with the FDA office of 

compliance are moving forward relative to resolving manufacturing practices. Both the 

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60

agency and MedImmune are confident that 7 million doses will be available this summer. 

2007 National Influenza Vaccine Summit

Dr. Mootrey provided an overview of this year's National Influenza Vaccine Summit, 

which took place on April 19 and 20. It has become an annual meeting co-sponsored by the 

American Medical Association and the CDC to discuss influenza vaccine issues with a broad 

stakeholder base. There were 190 attendees representing 74 organizations. The 

manufacturers estimated that, barring any unforeseen glitches in the system, up to 132 million 

doses of vaccine could be expected this year. Carol Baker described NFID's Childhood 

Influenza Coalition, the American Lung Association discussed its flu clinic locator and Tony 

Fiore presented a summary of the ACIP recommendations. Key issues discussed were the 

vaccine composition, the pediatric second dose, recommended groups, the remaining age 

groups, the potential time frame for modifying influenza vaccine recommendations, 

considerations for expanding those recommendations, and some future challenges as the 

recommendations were expanded. There was quite a bit of discussion of the fact that ACIP 

now recommends vaccination for persons, including school-aged children, who want to 

reduce the likelihood of becoming ill with influenza or transmitting influenza to others, 

should they become infected. 

There was an emphasis on supply and distribution issues, including the rationale for 

post-season shortages, supply challenges, and providers' misperceptions regarding the 

prioritization of vaccine delivery. The CDC presented some data from the secure data 

network indicating that private providers had received proportionately equitable supplies 

throughout the 2006-2007 season. 

One very active session had to do with legislation. Some legislative initiatives may 

present barriers to achieving coverage, for example, those that prohibit the use of thimerosal 

in vaccines. Others may complicate equitable distribution. Several proposals suggest 

prioritizing distribution to certain provider groups. There will be an effort to provide much 

needed education and information to lawmakers and community leaders. 

 Another session focused on increasing demand for vaccination through a variety of 

partnerships. Awards were given for immunization excellence in three different categories. 

For extending the season, the getaflushot.com organization received the award, and they 

partnered with an unusual group of food banks. The Virginia Mason Medical Center got the 

award for the healthcare worker partnership. Through their mandatory vaccination program, 

they have achieved 98 percent vaccination of all of their staff for the past two years. The 

seasonal activities award went to a Maryland elementary school influenza vaccination project; 

in some schools, more than 40 percent of the children were vaccinated using two different 

models and over 114,000 doses of vaccine were distributed. 

 As far as increasing vaccination coverage, there was a presentation showing how to 

measure vaccine use, followed by a discussion about the length of the season and how to 

expand it. Dates for the National Influenza Vaccination Week were presented for the first 

time. Throughout the meeting, there was discussion about the need for more timely and 

consistent messaging. Other items for discussion included how to better balance supply and 

demand; how to track discarded doses and possible ways to redistribute doses; ideal settings 

for vaccination; and ways to expedite and smooth out the vaccine approval, testing, and 

delivery process. 

 The executive committee of the Summit will continue to work on improving coverage 

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61

of healthcare workers and is also encouraging the formation of an informal legislative task 

force, whose primary intent would be educational. Another objective is to develop a simple, 

consistent statement on when and who to vaccinate. The current statement is, "The National 

Influenza Vaccine Summit encourages that every year influenza vaccine be administered to all 

people, including school-aged children, who want to reduce their likelihood of becoming ill of 

influenza or transmitting influenza to others as soon as the year's vaccine becomes available. 

Influenza immunization should continue throughout the influenza season through the winter 

months and beyond as long as vaccine is available.” Suggestions are welcome. 

 

Discussion

 Dr. Abramson noted that there had been a healthcare summit five years ago and not 

much progress had been made. Dr. Schaffner responded that the National Foundation for 

Infectious Diseases continues to promote healthcare worker immunization. However, with 

rare exceptions where institutions have been extraordinarily forceful and innovative in 

providing influenza vaccine and obliging all healthcare workers to participate, coverage 

remains at just about 50 percent. Nurses in particular are very reluctant to be vaccinated, 

based on an embedded myth that one can get flu from the vaccine. In addition, many 

prominent physicians remain skeptical about the efficacy of influenza vaccine. So any 

suggestions on how to move ahead are welcome. 

 Ms. Stinchfield reported that rates had increased by 10 percent in Minnesota using the 

declination form. They are also working on real time IT solutions to track who has come in, 

who needs follow up and who has filled out a declination form. The challenge is that the 

myths are very strong, very old, and mostly unfounded. The message that all vaccines are 100 

percent effective is not correct, but this in fact underscores the need to get everybody in so 

there will be a better immunized population. A simple message works best: Everybody needs 

flu vaccine. It is needed throughout the season. It will help healthcare workers as well as all 

the other high-risk populations. 

 Dr. Tan of the American Medical Association pointed out that the Summit executive 

committee was collaborating with some other organizations to provide a best-practices 

package, highlighting three to five facilities across the country that have successfully 

increased healthcare worker immunization rates, starting with the Virginia Mason program. 

Some of the techniques were very innovative but also very aggressive. The idea is to offer a 

variety of models that work. The Summit Web site -- www.preventinfluenza.org -- has a 

specific healthcare worker site with all the necessary resources, including a sample 

declination form that can be downloaded. It also has guidance from organizations such as the 

National Foundation for Infectious Diseases, the HICPAC-ACIP statement and the joint 

commission standard. 

 Dr. Poland noted that it has been shown that if it is mandated, healthcare workers get 

immunized. Out of 5,000 employees, Virginia Mason had only six leave over the policy. It 

would be unconscionable to allow a rubella-naïve nurse to work in a maternity ward because 

he or she had misconceptions about rubella vaccine, and this thinking should extend to 

influenza vaccine. It has also been shown that informed declination helps. Finally, trial 

attorneys now understand that multiple professional organizations have listed this as the 

standard of care. Unfortunately it may take a few well-publicized lawsuits to get everyone on 

board in terms of quality and patient safety. 

Dr. Lett wondered if there were any activities to educate legislators about influenza 

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62

vaccine, and in particular whether there was going to be an organized national effort. Dr. Tan 

replied that the Summit had already formed an informal task force, which had met twice 

regarding legislative issues across the country. An educational fact sheet on the challenges of 

influenza vaccine organization will be produced, including administration, supply, and 

distribution. Obviously, thimerosal will be another focus. 

Dr. Iskander noted that if healthcare workers are concerned they may get the flu from 

the vaccine, then perhaps it is time to study that issue in more depth rather just a lot of hand 

wringing. Dr. Abramson responded that the question of whether this was a safety issue had 

been raised with OSHA and their answer was, "We did not have proof that patients did not 

give the flu to healthcare workers." 

Dr. Sumaya said that if the healthcare system only relies on individuals to implement 

immunization schedules, coverage would always remain at 50 to 70 percent. Although it 

sounds militaristic, it might be necessary to make immunization more obligatory. Healthcare 

workers are familiar with the safety and quality issues, so it may be one place where there can 

be stronger urging, such as making immunization coverage part of hospital accreditation or 

part of individual performance evaluations. There would always have to be a mechanism for 

opting out, but the issue is something the ACIP could tackle. 

 Dr. Turner of American College Health thought there had already been an effort to 

consolidate messages and make them consistent. He asked whether last year’s vaccine 

production goals had been met, whether the messaging had resulted in an increased uptake

and whether there had been an appraisal or assessment of last year’s efforts. Dr. Wallace 

replied that manufacturers produced around 120 millions doses and that 102.5 million were 

distributed. He did not know how many doses were administered. 

 Dr. Decker suggested that NIOSH could take an active role in the influenza-amonghealthcare-workers issue and provide some science to guide OSHA. Dr. Landry of GSK 

added that this could be viewed as a quality-improvement measure for hospitals and that 

NCQA should be approached as well. 

 Dr. Abramson thanked Dr. Allos for her work on the influenza working group. 

USE OF VACCINES IN PERSONS WITH HIV/AIDS

Dr. Jane Seward, CDC/NCIRD/DVD

Dr. Gina Mootrey, CDC/NCIRD/ISD 

Children and Adolescents

Dr. Seward focused on changes made in the immunization schedule for HIV-exposed 

and infected children and adolescents. The term ‘exposed’ is used because infants cannot be 

called ‘infected’ until definitive testing has been done. New guidelines are being developed 

for prevention and treatment of opportunistic infections in this population, as a collaboration 

among CDC, NIH, and IDSA. The new guidelines will be divided into 2 documents, one for 

children and the other for adults. Accompanying the guidelines for children will be vaccine 

schedules for zero-to-six and 7- to 18-year-olds. Another group is developing the document 

for adults which will include the vaccine schedule for adults (≥ 18 years). Publication of both 

documents as MMWRs is expected sometime in the fall, but they will be updated on the Web 

as new data related to prevention and treatment of opportunistic infections become available 

and ACIP recommendations are passed. 

 The published 2007 immunization schedule for all children in the three different age 

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63

groups was modified with specific HIV language, taken from published ACIP 

recommendations. The footnote language was clarified in discussion with CDC subjectmatter experts. The colors of the bars on the immunization schedule were also changed, 

based on recommendations for HIV-status. Draft schedules were shared with CDC, NIH, and 

the IDSA working groups. The zero-to-six and 7-to-18 schedules were presented to the 

harmonized working group and they suggested that the ACIP vote on the schedules 

specifically because of the rotavirus language. There are no plans to harmonize the schedule 

with AAP and AAFP because of the small number of children involved. They suggested just 

staying with the ACIP recommendations. 

The rotavirus language is as follows: "No safety or efficacy data are available for the 

administration of rotavirus vaccine to infants who are potentially immunocompromised, 

including infants with HIV." (That language is right now in the footnote.) "Data are 

insufficient from the clinical trials to support administration of rotavirus vaccine to infants 

with indeterminate HIV status who are born to mothers with HIV/AIDS. Practitioners should 

consider the potential risks and benefits of administering rotavirus vaccine to infants with 

known or suspected altered immunocompetence." (That language includes HIV-infected 

infants.) 

 The existing language already provided the option for physicians to vaccinate after 

weighing the risks and benefits, but the "however" language supports vaccination of HIVinfected infants. 

 There are 6,000 to 7,000 HIV-exposed infants born each year in the United States. 

HIV status is not definitively known by six weeks, but most will be presumptively negative 

until they have been tested. They cannot be definitively negative until four months of age 

according to current guidelines. Only 100 or 200 will eventually test positive and those are 

basically infants of mothers who did not get any prenatal care and did not receive HIV 

prophylaxis during pregnancy. 

 Rotavirus is a ubiquitous infection in childhood. Virtually every child in this country 

and other countries will become infected by five years of age. So if these children are not 

vaccinated, they will certainly come down with wild rotavirus disease. RotaTeq is the only 

vaccine licensed in this country currently and that strain is considerably attenuated with a very 

low incidence of fever, other constitutional symptoms, or viral shedding. Available data 

suggest that rotavirus disease is not more severe in HIV-infected infants, which propelled the 

commencement of trials in HIV-infected children in Africa. 

 The same studies that showed no difference in disease severity did show higher allcause mortality in HIV-infected children during four weeks of follow-up after rotavirus 

illness, but the significance of that is unknown because it was not directly related to the 

rotavirus illness. 

 Most of the studies comparing rotavirus disease severity between HIV-infected and 

non-infected infants were done in infants, and more data are needed on disease severity in 

older, immunosuppressed HIV-infected children. It may be that in countries without good 

HIV treatment, there are differences as children become more immunocompromised. 

Oral polio vaccine replicates much more robustly in the intestinal tract with a much 

higher viral-shedding risk than RotaTeq, and it is considered to be safe and is immunogenic in 

HIV-infected children, according to two published studies. 

 No trials with rotavirus vaccine are planned for the U.S. in HIV-infected infants, 

mainly because there are not enough infants to do a study. In developing countries, where the 

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numbers of HIV-infected children are higher, co-morbidities are also higher, especially 

malnutrition, and the rotavirus disease mortality and burden are significantly higher. Trials 

with both the GSK and Merck rotavirus vaccines are under way or planned. It is not known 

when those data will become available, but presumably not anytime soon. 

The fact that no safety or efficacy data are available is in the ACIP statement already. 

However, the following considerations support vaccination of HIV-infected infants. One, the 

HIV diagnosis may not be established before the age of the first rotavirus vaccine dose. Only 

1.5 to 3 percent of HIV-exposed infants in the U.S. will eventually test HIV positive. Two, 

natural rotavirus infection does not appear to be more severe in HIV-infected infants. And 

three, RotaTeq vaccine is considerably attenuated. 

 When these data were presented to the NIH, CDC, IDSA group, there was 

considerable discussion about the safety of giving the vaccine to HIV-infected infants. Use of 

RotaTeq vaccine in HIV-exposed or infected children was discussed when vaccine policy 

recommendations were made by the ACIP. It was considered to be the intent of the ACIP to 

administer the vaccine to those infants, but the statement did not state that intent strongly. 

After the meeting, the group expressed discomfort with giving the vaccine to HIV-infected 

infants because of lack of safety and efficacy data. Another suggestion was to change the title 

of this schedule to “HIV-exposed and infected infants”. 

 The schedule for children age zero to six years follows the same order as the regular 

schedule with the following changes to some of the bar colors. For influenza, HIV status is 

considered one of the high-risk groups so this vaccine is recommended annually for HIVinfected children and the bar color is changed accordingly from purple (high-risk groups) to 

yellow (routine recommendation). For MMR and varicella, there is red language saying: "Do 

not administer to severely immunosuppressed children." For hep A and mening 

polysaccharide vaccine, these children are not in the high-risk group, but they could be if they 

had additional areas of residence or conditions, so the bar is left purple. They are potentially 

high-risk but not by virtue of their HIV status, so they should get PPV. The footnote 

language is absolutely word for word out of approved statements, except for rotavirus, which 

is a little different. 

 The vote is whether to approve the immunization schedules for both age groups and, 

as new ACIP recommendations are made, to incorporate them into the schedule after 

publication of provisional or final ACIP recommendations. The options for rotavirus vaccine 

language are to adopt the new language presented above, use exact language from the ACIP 

statement, which says to weigh the risk and benefits but it can be given, or recommend that 

the vaccine not be administered until safety and immunogenicity efficacy data are available. 

Discussion

 Dr. Baker thought the comment about exposed and infected children was a good one, 

since the rotavirus schedule is to be completed by 32 weeks of age, before it can be 

established whether children are infected. In addition, the first 32 weeks are when CD4 

counts are very good. She favored the implicit recommendation from the rotavirus schedule; 

it is a benefit to children in general and why should HIV-infected children get less benefit 

than regular children under these circumstances? 

 Dr. Gilsdorf brought up her suggestion from the previous day about the use of the 

word "recommended" in the title because it suggests that all of the bars represent 

recommendations from the ACIP. She felt that there was a difference between a 

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65

recommendation and support. Dr. Schuchat clarified that the previous discussion had focused 

on adults and that the committee was staying away from recommendations on certain of the 

adult vaccines for the HIV-infected population because data were forthcoming, for example 

for zoster and HPV. That language is much more critical for the adults where there is a large 

HIV-infected population that is looking for guidance and there are more data available. Dr. 

Gilsdorf also noted that the wording for HPV should indicate females only. 

 Dr. Treanor pointed out that when the original rotavirus recommendation was made, 

the vaccine had not been used extensively; now that there has been extensive use of the 

vaccine without problems, people are more comfortable. However, regarding the fact that 

rotavirus disease is not more severe in HIV-infected children, there is the possibility that 

people will conclude that there is no special reason to vaccinate. His recommendation for the 

wording would be to just leave out No. 2. Dr. Baker affirmed that suggestion. 

 Dr. Morse asked about the footnote that says only TIV should be used for HIVinfected persons. Dr. Seward clarified that it was strongly recommended that their contacts 

get vaccinated, and they can get LAIV. Dr. Morse thought that was confusing. His second 

question was whether revaccination for PPV should be offered or recommended. Dr. Seward 

affirmed that ‘offered’ was the exact language. The data on safety and immunogenicity of 

PCV for children aged 2 to 18 years will be presented in the fall and if it is voted on, it could 

change the PCV recommendation. 

 Dr. Sumaya asked whether natural rotavirus infections appear to produce similar 

levels of severity in HIV-infected as in non-infected HIV infants and, if so, that needs to be 

more clearly stated. Dr. Baker responded that there are actually not strong enough data to say 

anything. 

 Dr. Offit from Children’s Hospital of Philadelphia emphasized that rotavirus vaccine 

is a very highly attenuated strain and a pentavalent vaccine. It is 1.6 times 10 to the sixth 

platform units per strain and there are five strains, so 8 million infectious particles are given 

by mouth. However, less than 10 percent of children shed and they shed for, at most, a day or 

two and in very limited quantities. Oral polio vaccine or RotaShield shed to a greater extent. 

This is now the only live attenuated viral vaccine given routinely to young infants. Typically, 

severe combined immunodeficiency disease is not a diagnosis made until about eight months 

of age. Since children with SCIDs are clearly getting this vaccine, it would be interesting to 

see whether they have increased or prolonged shedding associated with symptoms. 

 Dr. Halsey from Johns Hopkins said he was surprised to hear the discussion about 

whether these were recommendations. The public needs clear recommendations and it would 

be more efficient than having to revise other statements. 

Dr. Pickering said the transcript of the rotavirus meeting indicates a preference that 

rotavirus vaccine be given to children who are born to mothers who are HIV exposed. Dr. 

Parashar added that a number of studies had looked at viral shedding and immunologic 

response in HIV-infected and noninfected children, and the disease severity by a variety of 

parameters was identical in both groups. Both mounted equally good immune responses to 

natural infection--about three-fourths of infants in each group. Shedding was slightly longer 

in HIV-infected kids, but most of it was asymptomatic. So they concluded there really was no 

difference in the natural history of rotavirus infection in HIV versus non-HIV kids. 

Dr. Rathore of Jacksonville, Florida suggested that many practitioners, particularly for 

HIV-exposed children, may already be using rotavirus vaccine in these children because his 

practice had not seen an infected child in ten years. 

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66

Vote

Dr. Baker made a motion to accept Dr. Seward’s recommendation with the edits that 

had been discussed. Ms. Stinchfield seconded the motion. Dr. Gilsdorf asked whether this 

motion addressed the concerns about the difference between a full recommendation and 

support of use. Dr. Schuchat responded that the distinction was not critical for pediatric 

cases, but it was important for adults. Dr. Seward thought that with live viral vaccines more 

data might be needed, but not with inactivated vaccines. An unidentified speaker suggested 

using a different color, indicating that the recommendations is being made without data. Dr. 

Pickering suggested referring the question back to the respective work groups for 

consideration of the wording change in the title. 

 Dr. Seward summarized the motion, which was that ACIP approve the immunization 

schedule for HIV-infected children -- exposed and infected children zero to six years and 7 to 

18 years, with the changes in the footnote as suggested for rotavirus and for influenza and that 

new ACIP recommendations will be incorporated into the schedule after publication of 

provisional recommendations. Edits include using “exposed or infected” and specifying 

females for HPV. 

Dr. Morse: yes.

 Dr. Treanor: abstain. 

 Dr. Sumaya: yes. 

Ms. Stinchfield: yes. 

 Dr. Neuzil: abstain. 

 Dr. Morita: yes. 

 Dr. Lieu: yes. 

Dr. Lett: yes. 

 Dr. Hull: yes. 

 Dr. Gilsdorf: yes. 

 Mr. Beck: yes. 

Dr. Baker: yes. 

 Dr. Allos: yes. 

 Dr. Abramson: yes. 

Adults 

Dr. Mootrey then showed the recommended schedule for HIV-infected adults. One 

difference between the children and adults was that there was already a schedule for children, 

which just had to be modified. The adult schedule is a new addition to the guidelines and it 

has not been brought to the ACIP adult immunization work group yet. There should be an 

updated draft for the opportunistic infections adult work group by the end of the summer. 

 Dr. Morse commented that there should be consistency across the tables for the “Do 

not administer” recommendation. 

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67

UPDATE ON ROTAVIRUS VACCINES

Dr. John Treanor, ACIP, Working Group Chair 

Dr. Umesh Parashar, CDC/NCIRD/DVH

Dr. Penina Haber, CDC/ISO

Dr. Manish Patel, CDC/NCIRD/ISD

Dr. Hector Izurieta, FDA/CBER

Dr. Treanor announced that he would be rotating off ACIP and wished his successor 

luck in chairing the rotavirus working group. 

Safety Monitoring Update 

Dr. Haber provided a summary of RotaTeq vaccine adverse events reported to 

VAERS, followed by updates on the Vaccine Safety Datalink and Merck Phase IV study. 

From March 2006 up to June 14, 2007, about 6.2 million doses of RotaTeq were distributed. 

During the same time period, VAERS received a total of 1,251 reports of adverse events 

following RotaTeq vaccination. Of those, 573 (46%) were from RotaTeq given alone, and 

609 (47%) were after the first dose. The most frequently reported outcomes were diarrhea, 

vomiting, fever, and hematochezia. 

 Of all the reports, 9.4 percent or 117 were confirmed intussusception reports. Thirtyeight were within 1 to 21 days after vaccination and of those, 23 were within one to seven 

days. No intussusception deaths were reported. 

 Dr. Haber described 116 cases in a graph, which showed a couple of peaks but no 

major pattern. When intussusception reports are analyzed by dose distribution of 

intussusception and by onset interval in days, there again is no major pattern. After the FDA 

notice on February 13th, 2007 and following the MMWR publication in March, reports to 

VAERS of events occurring over 21 days increased, which indicated higher reporting 

efficiency to VAERS. 

 Overall, the mean age at symptom onset symptom was 23 weeks, the range 9 to 45 

days. There was equal distribution between male and female. Fifty-seven or 49 percent had 

contrast enema, 32 percent (37) had surgical reduction, and 16 percent (19) had surgical 

resection. Two experienced spontaneous resolution, and for two reports there was no 

information. 

 Dr. Haber then provided an update on the Vaccine Safety Datalink. From May 21, 

2006 up to June 17, 2007, 68,858 vaccinations were given and there was no report of 

intussusception within 30 days post vaccination. An analysis of distribution by age and dose 

by age shows that almost 50 percent of vaccinations were Dose 1, and about 30 percent were 

Dose 2. 

Dr. Haber gave an update on the Merck RotaTeq post licensure safety study. This is a 

prospective observational active surveillance. The study population is a large insured U.S. 

population with annual birth cohort of about 100,000, and the planned final study size is about 

44,000 vaccinated children. The study plan is to monitor rates of intussusception and overall 

vaccine safety, comparing the rates of several control groups 30 days post vaccination for 

each dose. 

So far, there have been 7,196 RotaTeq recipients through the third quarter of 2006. As 

of December 31st, 2006, there were no cases of intussusception in RotaTeq recipients, but 

there were three cases in controls. The next review will include about 18,000 RotaTeq 

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recipients vaccinated from February 2006 to December 2006. 

 

Data Interpretation

Dr. Patel focused on whether the observed number of cases exceeded what would be 

expected to occur by chance alone. Intussusception rates vary in the first six months of life 

when the vaccine is being administered, so age stratification must be taken into account for 

the calculations. 

Dr. Patel first talked about the calculations for the 1- to 21-day window. VAERS 

received reports of 38 cases of intussusception occurring within 1 to 28 days of vaccination, 

whereas approximately 99 cases would be expected to occur by chance alone, after adjusting 

for age. The reporting rate ratio is 0.37, with the upper 95 percent confidence limit being less 

than one. Data assumptions are 100 percent reporting completeness and 100 percent 

administration of the doses distributed. In each of the three age groups, the observed numbers 

did not exceed the expected.

 For the one- to seven-day window, VAERS has received reports of 23 cases of 

intussusception, whereas approximately 33 cases would be expected after adjusting for age. 

The reporting rate ratio for the one- to seven-day window was 0.67, which is higher than for 

the 21-day window. However, the upper 95 percent confidence limit was 1.08. Within each 

of the three age strata, observed numbers did not exceed the expected, but for the 6- to 14-

week age group, the number of observed cases was the same as the expected number. 

 Most of the RotaShield action occurred during the first week of vaccination with Dose 

1. For Dose 1 of RotaTeq, in total, there were 12 cases observed in VAERS after Dose 1 and 

one would expect approximately 12 background cases within seven days of vaccination using 

the same 100 percent assumptions. With RotaTeq, it appears that Dose 1 is generally being 

administered according to the ACIP recommendations, at 6 to 12 weeks of age. The VSD 

data show that 93 percent of the doses were administered in the 6- to 14-week age group and 

the majority of the Dose 1 cases were also in that age group (10 of the 12 cases). Only two 

cases occurred in the second age group (15- to 23-weeks). 

 The RotaShield Dose 1 experience was quite different: 80 percent of the reported 

VAERS cases for RotaShield were after Dose 1, suggesting a clustering effect after Dose 1, as 

opposed to RotaTeq, where only 34 percent occurred after Dose 1. Eighty percent of the 

RotaShield Dose 1 was administered to children older than 90 days or 12 weeks of age, 

whereas only 7 percent of the RotaTeq in VSD has gone to children over 90 days old. 

 The nationwide case-control study for RotaShield revealed a 37-fold risk for Dose 1 

within three to seven days of vaccination, whereas no similar signal has been seen with 

RotaTeq yet. 

 An important question is, of all the cases that are actually occurring within 1 to 21 

days of vaccination, how many are being reported to VAERS? Looking at all intussusception 

cases reported to VAERS by onset month, two-thirds were outside the 1- to 21-day window, 

which is when vaccine is unlikely to be biologically linked to intussusception. The FDA 

notification in February did stimulate reporting, but most of the reports in the two months 

since the FDA notification were also outside that 1- to 21-day risk window, which suggests 

that reporting efficiency is high for the first 21 days of vaccination. 

 A second data assumption has to do with vaccine administration, and the question is, 

what proportion of the doses that are distributed is actually being administered? RotaTeq has 

been on the market for approximately 16 months and two factors suggest favorable vaccine 

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69

uptake. One is that the manufacturer has been distributing 400,000 to 600,000 doses of 

vaccine per month for the past eight months and the other is that the VFC contract now has 

been in place for about a year. The National Immunization Survey after RotaShield showed 

that 66 percent of the vaccine doses distributed were actually administered during the nine 

months it was on the market. 

 In order to do the sensitivity analysis, the assumption was that reporting completeness 

was around 75 percent and that 75 percent of the doses distributed were actually administered. 

With these assumptions, the reporting rate ratio is 0.7 for the 1- to 21-day window, and 

slightly above 1 for the 1- to 7-day window. But neither of these is statistically significant. If 

the reporting completeness was 50 percent and vaccine administration was 50 percent of the 

doses distributed, one would begin to see a signal. For the 1- to 21-day window, the reporting 

rate would be 1.47, and for the 1- to 7-day window, the reporting rate would be 2.6. Despite 

these assumptions, the reporting rates are still rather small. 

 Looking at all intussusception cases by onset interval in days, more cases have been 

reported during Week 1 compared to Weeks 2 and 3. There are several possible explanations 

for this clustering effect. One is the well-known effect of passive surveillance of adverse 

events, where reporting tends to be better closer to the exposure. Another possibility is that 

this clustering could represent a two- to three-fold risk in Week 1 compared to Week 3. Week 

1 clustering could be also a random event. However, since the number of cases is small by 

week, one should be cautious in over-interpreting those data. 

 In summary, no intussusception signal has been identified with post-licensure 

monitoring for RotaTeq in the U.S. To date, the combined safety data include the 105,000 

doses for the REST clinical trial; about 70,000 doses for the VSD; 7,000 Merck postlicensure 

doses; and 16 months of VAERS data, none of which has identified a signal. However, one 

must be cautious and continue monitoring because the current data cannot exclude smaller 

magnitudes of risk, which would require large sample sizes. If one wanted to exclude a fivefold risk in the first week of vaccination, for example, one would need follow-up data on 

nearly 130,000 vaccinees. However, to exclude a two- or three-fold risk, follow up data for 

one week on 400,000 to 1.3 million vaccinees would be needed. Even a case-control study 

would be fairly cumbersome to rule out such a magnitude. 

To place this risk in perspective, if there was a two- to three-fold risk after Dose 1 and 

the entire U.S. birth cohort of 4 million were to receive that dose, one would see 

approximately 25 to 50 additional cases per year. In contrast, approximately 50,000 to 70,000 

rotavirus hospitalizations would be prevented and possibly 20 to 60 deaths from rotavirus. 

 To reiterate the conclusions from the previous ACIP meeting in February and the most 

recent MMWR, the observed reporting rates of intussusception do not appear to be greater 

than what would be expected to occur by chance alone. Nonetheless, these data must be 

interpreted with the limitations of the passive surveillance system in mind. Ongoing 

monitoring will be crucial, particularly for Week 1 after vaccination, where there may be a 

clustering effect. Finally, it will be important to continue to follow VSD and Merck postlicensure cohorts, because a larger cohort would be needed to exclude smaller risks. 

RotaTeq and Kawasaki Disease: Pre- and Post-Licensure Experience

Dr. Izurieta presented data from a study done by a number of investigators and 

groups, including the CDC, the Vaccine Safety Datalink group and the FDA. As background, 

he explained that the original FDA-approved label did not include Kawasaki disease cases. In 

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70

the original license application were three cases in the vaccine group, and zero in the placebo 

group. In the four-month safety update, there were five in the vaccine group, and zero in the 

placebo group. Following an inquiry from the Swiss regulatory agency, an FDA review of 

Kawasaki disease showed a total of five cases in the vaccine group, and one in the placebo 

group. The placebo was from Finland, and the vaccine cases were all from the same center in 

the U.S. None were of Asian descent. All cases were between 12 and 22 weeks of age and 

all, except for the placebo, had received other concomitant childhood vaccinations. All but 

the placebo case completed the series of three doses of vaccine. 

 When the label revision was made in 2007, Kawasaki disease was reported among the 

serious adverse events. For each dose in the Phase III clinical trial, infants were followed for 

up to 42 days. Kawasaki disease was reported in 5 of 36,000 vaccine recipients and 1 of 

35,000 placebo recipients. The difference was not statistically significant. 

 Regarding the post-marketing experience, there were reports of Kawasaki disease, but 

this does not mean there is or is not an association. No changes were made in the indications, 

warnings or precautions regarding the use of this vaccine. 

In the U.S., Kawasaki disease is the leading cause of acquired heart disease in 

children, with over 4,000 cases every year. Almost 80 percent of these children are under five 

years of age. The incidence in children under five, as reported by Dr. Belay in a 2000 

Pediatric Infectious Disease Journal article, was between 9 and 19 per 100,000 per year. 

Recent unpublished data from the Kids Inpatient Database for 2003 showed an incidence of 

21 per 100,000 for all children under one year of age and 11 per 100,000 per year for children 

under six months of age. Data are missing from 20 percent of the children for specific age in 

months, so the 11 per 100,000 for children under six months of age could be underestimated. 

 The disease has not been reported in association with vaccinations, but in 1983 

Japanese investigators reported finding rotavirus particles or capsomers in 29 of 39 (74%) 

stool specimens obtained within a few days of admission for Kawasaki disease to a Tokyo 

hospital. These patients did not necessarily have gastrointestinal symptoms. In the control 

group, which did not have Kawasaki, the rates of finding rotavirus particles were much lower. 

There are no confirmatory studies in the literature. 

 Again with regard to the postmarketing experience, there were four reports to VAERS 

following RotaTeq vaccination as of June 19, 2007. Three were received before the FDA 

notification and one after notification. 

 Approximately 6 million RotaTeq doses had been distributed in the U.S. of June 6, 

2007, therefore the reported rates from the passive surveillance system are, in fact, lower than 

what would have been expected. This is subject to the limitations of any passive surveillance 

system, including VAERS. In addition, providers may not associate Kawasaki disease with 

vaccines and will not necessarily report them. 

 Of the four suspected Kawasaki disease cases identified in VAERS, one was a female 

of Korean descent, who was almost three months old at first dose. She had some symptoms, 

but not enough to be considered classic Kawasaki disease. The patient was treated by a wellknown Kawasaki expert from Hawaii. 

The second case was a black Hispanic from Texas, almost three months old as well. 

For the first dose, there was a three-day interval between vaccine and onset of symptoms. This 

patient had all the classic symptoms for Kawasaki except adenopathy, and also had coronary 

ectasia. The patient was treated by intravenous immunoglobulin. 

 The third case was from North Carolina, a six-and-a half-month old, with some classic 

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71

symptoms after the third dose. But the conjunctival injection was yellowish, and the patient 

was diagnosed originally as having a bad rash. It is not known whether this case will be 

considered confirmed or not. 

 Information on Case No. 4 is incomplete. The report is for a male from California, five 

months of age, with onset 14 days after vaccination. The medical chart has not been received. 

All four cases described received other childhood vaccines as well. 

There has been an ongoing review of all suspected Kawasaki disease reports to 

VAERS since it started in 1990. Out of 81 suspected Kawasaki cases after all vaccines, 44 

were from the U.S. Of those 44, 19 were among children less than a year old, and 13 were 

under 16 months of age. Again, this does not mean they are confirmed Kawasaki disease or 

that they are causally associated with vaccination. 

The CDC's Vaccine Safety Datalink study data come from six of the VSD sites. There 

was one unconfirmed Kawasaki disease case, meaning no chart review was made, out of over 

68,000 doses of vaccine. This was within the expected rate, which would have been around 

two cases. VSD has agreed to incorporate Kawasaki disease into the ongoing Rapid Cycle 

Analysis of RotaTeq adverse events, as they have done with intussusception. 

 Merck has provided preliminary data from their observational Phase IV study. As an 

agreement for licensure, They agreed to an approximately 44,000 study population, and 

Kawasaki is incorporated. So far, for the primary analysis window of 30 days after 

vaccination, no Kawasaki disease or vasculitis cases have been found in the 7,000 RotaTeq 

vaccinees or in the 14,000 concurrent controls. 

 In summary, the signal from the pre-licensure clinical trials is now captured in the 

label. The Kawasaki reports in VAERS are within what would have been expected, but risk 

cannot be excluded. The ongoing observational studies from the VSD and the Phase IV show 

reassuring data, but they are limited because of insufficient power. One will have to wait 

until these studies progress to be able to reach conclusive results. At this time, there is no 

cause-and-effect relationship established between Kawasaki disease and RotaTeq or any other 

vaccine. FDA, CDC, and Merck will continue to monitor the safety of RotaTeq vaccine using 

VAERS, VSD, and the Merck Phase IV data. 

Discussion

Dr. Baker asked whether fever was part of the criteria for reporting the second case. 

Dr. Izurieta replied that the patient had fever for five days. Dr. Baker then asked whether all 

four patients had cardiac echoes and when. Dr. Izurieta replied that the Texas case did. Dr. 

Baker noted that coronary ectasia was one of those things that may resolve. Dr. Izurieta 

replied that sometimes there is no evidence of ectasia or the evidence comes later and then 

resolves if the patient is treated early.

 Dr. Baker then asked if other etiologies were excluded in the chart reviews. Dr. 

Izurieta replied there was not enough information on all the VAERS cases. The case from 

North Carolina had an alternative diagnosis and the case from Hawaii also had otitis. Only 

the Texas case was really classic. Dr. Baker said that it was very difficult to distinguish 

Kawasaki from certain viral etiologies, especially in children under six months of age. Even 

classic cases may have an alternative infectious disease diagnosis. On the other hand, those 

are the patients more likely to have an atypical presentation of Kawasaki disease where the 

physician may not make the diagnosis. This is a very complex association, so it is good that 

the rapid cycle safety analysis will be performed. 

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72

 Dr. Abramson confirmed that children less than six months of age more often than not 

have atypical Kawasaki and those who really have Kawasaki disease also have a higher 

incidence of coronary aneurism. He felt it was imperative to look for those children with the 

atypical Kawasaki, even though it might require outside expertise. 

 Dr. Gentsch emphasized the importance of standardizing case definitions for adverse 

events because, unlike efficacy, safety cannot be measured directly. It can only be inferred 

indirectly from measuring multiple, different adverse events. Without standardization, there 

is a lot of heterogeneity and lost data. He added that pre-licensure safety processes can be 

improved or standardized using lessons learned from RotaShield, where there was a similarly 

small number of events--about five in the vaccinated and one or two in the unvaccinated 

placebo group. They did a simple 2-by-2 chi square, and the P value was not significant. But 

some of those five cases were clustered around the same time. So a person-time analysis, 

while not statistically significant, would have been closer to significance. If a person-time 

analysis was not taken into account in the pre-licensure data, it should be in the future. 

Dr. Pickering asked whether the three cases for which data were available were 

already symptomatic when immunized. Dr. Izurieta replied that one had what appeared to be 

a bad rash, onset date unknown, but all of the other symptoms appeared after vaccination, 

from a few hours up to Day 14 in Case No. 4. 

Dr. Iskander clarified that VAERS specifies onset as the first symptom, whereas the 

standard criteria for Kawasaki define it as the onset of fever. Dr. Slade added that one child 

had an onset of fever at 12 hours after vaccination, but none were symptomatic at the time of 

vaccination. 

Dr. Gellin asked what it takes to get something included in the label initially. He also 

wondered how robust the Kids’ Inpatient Database (KID) was. Dr. Houn replied that the 

adverse reaction section of the label was governed by 21 C.F.R. 201.57(c)(7), which says that 

adverse reactions identified for clinical trials, especially those with significant clinical 

implications, must be supplemented with additional details, such as frequency or nature. 

 Dr. Iskander said KID more typically uses either the VSD or the HCUP (Healthcare 

Utilization Program) databases, but they are happy to work with any and all databases that 

provide reasonable background rates. 

 Dr. Abramson asked whether there would be a study design to compare those who get 

every immunization but rotavirus with those who get every immunization including rotavirus. 

Dr. Gargiullo replied that Ermias Belay was planning to look at all cases of Kawasaki 

syndrome going back to 1992 and one of the hypotheses would be live vaccine versus 

inactivated. 

UPDATE: HPV VACCINES

Dr. Janet Gilsdorf, Chair, HPV Working Group 

Dr. Gary Dubin, GlaxoSmithKline

Dr. John Iskander, CDC/ISO

Dr. Lauri Markowitz, CDC 

Dr. Gilsdorf reviewed the activities of the working group to date. In June 2006, the 

ACIP voted on the recommendations for the quadrivalent HPV vaccine. These provisional 

recommendations were available on the Web in July 2006, and the HPV vaccine official 

statement was published in the MMWR in March 2007. The recommendations have since been 

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73

adopted by a number of other collaborating organizations. 

 The working group has continued to meet monthly to review the bivalent HPV vaccine 

for safety, immunogenicity, and primary and secondary endpoints. The GSK bivalent vaccine 

BLA has been submitted to the FDA, so the working group has also considered future 

recommendations to be addressed with the predicted licensure of the bivalent vaccine. 

Post Licensure Vaccine Safety Data

Dr. Iskander provided an overview of postlicensure safety surveillance for Gardasil, 

the first U.S. vaccine licensed for human papillomavirus, and summarized available data from 

the Vaccine Adverse Event Reporting System and the Vaccine Safety Datalink. 

Gardasil is an inactivated vaccine, which was licensed by the FDA in June 2006 with 

an age indication of 9 to 26 years old and was subsequently recommended by the ACIP for 

routine use among 11- to 12-year-old females. General safety data were collected from 

almost 12,000 vaccine recipients in pre-licensure trials, and more detailed safety data were 

obtained from a subset of over 5,000 girls and women. Adverse reactions noted more 

commonly among vaccine recipients compared to placebo were injection-site pain, swelling, 

and erythema. Serious adverse events were rarely reported during pre-licensure trials. 

Among the ten deaths that occurred among Gardasil recipients, cause of death varied and did 

not appear plausibly related to vaccination. A total of four thromboembolic events were 

reported among vaccine recipients and six among placebo recipients. There was one fatality 

in each study group. Both involved oral contraceptive use, a known risk factor for 

thromboembolism. 

 Post-licensure safety data primarily focused on VAERS reports of commonly reported 

as well as serious adverse events, as defined in the Code of Federal Regulations. Reports 

involving population subgroups of special interest were analyzed separately. The data 

presented encompassed the first 11 months of the U.S. experience with Gardasil. Distribution 

data were obtained from the vaccine's manufacturer, Merck. 

 The vast majority of VAERS reports involved females and 70 percent covered the 

indicated age range of 9 to 26 years. Nearly 90 percent of reported events concerned Gardasil 

used as a single vaccine. Most reported adverse events that specified dose number followed 

the first dose in the series, however a substantial minority did not indicate the dose number. 

Reports to manufacturers, which typically originate from healthcare providers, make up the 

majority of reports to VAERS. Following a pattern typically seen within VAERS, a 

substantial proportion of reported adverse events begin on the day of or within a few days 

following vaccination. The most commonly reported events following Gardasil were fever, 

dizziness and loss of consciousness, also coded as syncope. Reports typically involved more 

than one adverse event, but only 5 percent of all reports were classified as serious. 

Dr. Iskander then presented clinical details of four deaths following Gardasil. Case 

No. 1 was originally reported as being due to influenza A virus infection. Case No. 2 

involved preliminary embolism in an oral contraceptive user. For Case No. 3, no additional 

medical records or clinical information were provided to VAERS, despite multiple attempts at 

follow-up. Case No. 4 involved laboratory-confirmed influenza B virus infection along with 

MRSA infection and has been reported to the national surveillance system for pediatric 

influenza-associated deaths. 

 Among 13 Guillain-Barre syndrome reports, nearly half have involved coadministration of meningococcal conjugate vaccine (Menactra®). Only two GBS reports that 

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74

meet the Brighton Collaboration case definition have followed Gardasil given as a single 

vaccine with symptom onset within six weeks following vaccination. 

 Eleven serious reports have involved syncope, all occurring within ten minutes of 

vaccination. There have been two documented instances of intracranial hemorrhage and three 

non-serious reports of confirmed nasal fractures. (ACIP recommends a 15-minute waiting 

period following all vaccines. Also, syncope is a common condition with a variety of triggers 

among young adults.) 

 Two additional reports involved thromboembolism. Case No. 2 involved multiple risk 

factors for thromboembolism, including a medical one of OCP use, an environmental one of 

air travel, and multiple documented genetic risk factors. Incidence of thromboembolism in 

OCP users varies across studies. Risk increases with age and smoking and is also higher 

during initiation of medication use, regardless of age. 

 VAERS reports among preadolescents involved commonly reported local and 

systemic non-serious events. The one report of Stevens-Johnson syndrome was poorly 

documented. 

 Through the end of March 2007, more than 5 million doses of vaccine have been 

distributed in the U.S. Age-specific dose-distribution data are not available. Within the 

Vaccine Safety Datalink, three-quarters of vaccine use has occurred among females under age 

18. Safety endpoints being monitored through rapid-cycle analysis include a range of events 

identified through prelicensure study and/or events that commonly occur among the target age 

group for this vaccine. The quadrivalent HPV vaccine is now covered under the Vaccine 

Injury Compensation Program. 

 The vaccine safety data presented should be considered as one of a variety of sources 

of post-licensure surveillance for this vaccine. VAERS data may be available more rapidly, 

but is subject to data quality and other concerns. CDC will continue to collaborate with FDA, 

the World Health Organization, and other public and private entities on post-licensure 

surveillance and communication activities. 

Efficacy and Safety Data – Bivalent HPV Vaccine

Dr. Dubin presented the results from an interim analysis of GSK’s largest single 

efficacy study, referred to as HPV-008. The GSK cervical cancer candidate vaccine contains 

HPV 16 and 18 virus-like particles, 20 micrograms of each VLP type, and is adjuvanted with 

AS04 adjuvant. The AS04 adjuvant was selected because its use resulted in higher levels of 

immunogenicity when compared to an aluminum hydroxyl adjuvant. 

Based on these early results, GSK initiated a rather large Phase III development 

program that included immunogenicity and efficacy studies. The immunogenicity studies 

take data from the efficacy studies been conducted in women between the ages of 15 and 25 

years, and then extend that through immunogenicity bridging to younger girls and women 

over the age of 25 years. The first efficacy study, HPV-001, has been reported on 

extensively. A second study called HPV-007 has now followed women in a blinded fashion 

through five and a half years following receipt of the first dose of vaccine. 

 There are two other efficacy studies. One is being conducted in Costa Rica by the 

U.S. National Cancer Institute, and that has approximately 7,500 subjects enrolled; the other 

is the HPV-008 trial, the subject of this presentation. In 2006, GSK started another efficacy 

study, which has enrolled over 5,700 women over 25 years of age. 

 Results from previous studies have shown that the GSK candidate vaccine is generally 

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well tolerated and is highly efficacious in preventing HPV 16 and 18 endpoints; it was up to 

100 percent effective in preventing CIN lesions and persistent infections associated with HPV 

16 and 18 in fully vaccinated women and also prevented abnormal cytologies in women in 

these studies. 

 The previous efficacy study presented primarily assessed the vaccine in women who 

were screened and were naïve to oncogenic HPV types at study entry. In the older studies 

protection or cross-protection has been observed against incident infection with a number of 

HPV types that are phylogenetically related to HPV 16 and 18, including types 45 and 31, the 

third and the fourth most common types associated with cervical cancer. Immunobridging 

studies have also demonstrated good immunogenicity of the vaccine in younger women down 

to the age of ten and in women over 25 years of age, with titers in the range associated with 

protection in the long-term follow-up study. 

 The recently conducted HPV-008 study enrolled 18,644 unscreened women age 15 to 

25 in North and South America, Europe, and the Asia-Pacific region, including Australia. 

The cohort included women with current or prior oncogenic HPV infections. This broad, 

unscreened population was thought to represent the kind of target population the vaccine 

ultimately will be used in.

Women were enrolled regardless of baseline cytological abnormalities. Many were 

infected with oncogenic HPV and many of these were non-vaccine types, although there were 

some with vaccine types as well. The interim analysis only excluded women found to have 

high-grade cytology abnormalities at the entry visit. It included all events reported in women 

who have received at least one dose of vaccine. 

 Regarding baseline characteristics, 90.5 percent of women had normal cytologies and 

the rest had abnormal cytologies, the majority of which were low grade. The half a percent of 

women with high-grade cytology abnormalities were immediately referred for colposcopy. 

Among women with normal cytologies at entry, about 15 percent had high-risk HPV, but 

women with low-grade cytology abnormalities or high-grade cytology abnormalities had 

progressively increased risk of having oncogenic HPV infection at entry; 91 percent of 

women with high-grade cytologies at entry were found to have high-risk HPV infection. 

 The women enrolled in this double-blind study were randomized one to one. The 

control vaccine was an adapted formulation of hepatitis A vaccine given on a three-dose 

schedule, which visually appeared identical to the active vaccine under investigation. Ten 

visits were scheduled over a 48-month period of time. The three-dose schedule was 

administered at zero, one, and six months. Blood samples were collected periodically for 

serology and cervical samples were collected at six-month intervals. The cervical samples 

were routinely tested for HPV infection and also used to assess cytologies. Management of 

women with abnormal cytologies was according to a prespecified algorithm. 

 The mean follow-up time when the interim analysis was triggered was 15 months 

following receipt of the first dose of vaccine. This is a relatively early time point in the 

planned longitudinal follow-up, which will extend through about 48 months. 

 When the women with high-grade cytology findings and those who were missing 

cytologies were eliminated, a total of 18,525 women remained for evaluation of efficacy. 

Immunogenicity was assessed randomly in a pre-specified subset of subjects that was 

representative for the regions participating in the study. 

 The primary endpoint of the study was to assess efficacy of the vaccine and the 

prevention of histopathologically confirmed CIN2+ associated with HPV 16 or 18 in the 

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76

cervical lesion. Diagnosis of CIN2+ was confirmed by a consensus-panel diagnosis, using 

three independent histopathologists who had been trained to evaluate these lesions. This was 

separate from the routine panel that assessed the results in a real-time frame to help guide 

subject management. 

 The methodology used to detect HPV 16 and 18 DNA in the lesion involved the use of 

a broad-range consensus primer system, referred to as the SPF-10 system, and detection was 

done by a line-probe assay. This SPF-10 system actually detects 14 oncogenic HPV types--

16 and 18 plus 11 nonvaccine types, which were routinely evaluated in all samples collected. 

In addition, type-specific PCR was done for HPV 16 and 18 to supplement the broadconsensus primer PCR. 

 A sample was considered positive if HPV 16 or 18 DNA was detected using either of 

the two methods. Women who were HPV-DNA negative and sero-negative were assessed at 

study entry in the primary endpoint analysis. If a woman was HPV 16 DNA positive or 

seropositive at entry and subsequently developed an HPV CIN2+ lesion, she was not counted 

in the final efficacy evaluations. However, if she developed an HPV-18-associated CIN2+ 

lesion, she was counted. The use of broad-spectrum PCR in a population of women that was 

broadly defined and included many women with prevalent infections with other types at entry 

allowed the study to fully characterize lesions for vaccine and nonvaccine types. 

The interim analysis was event-triggered, defined as whenever 23 HPV 16 or 18 

CIN2+ lesions were detected in the total vaccinated cohort. The final analysis will also be 

event-triggered and will generate additional data on CIN2+ outcomes. GSK intends to 

continue blinded follow-up for up to four years. 

 A high rate of prevalent HPV infections was observed at study entry, even in women 

with normal cytologies. Of the 23 lesions that triggered the interim analysis, 14 or 61 percent 

showed more than one HPV type detected in association with the lesion by PCR. Fourteen of 

the 23 lesions were derived from infections detected prior to completion of the three-dose 

series. The third dose is given at the Month-6 visit, which means the infections were acquired 

very early in the trial. The high rate of multiple infections in CIN lesions was not expected, 

based on published natural history literature or vaccination trials, so this was a unique 

observation, based on evaluating the HPV types across all lesions and all subjects in all 

cytology samples. 

 The 23 cases could be described by three patterns of HPV detection in the lesion and 

also considering HPV types detected in samples collected prior to detection of the lesion. The 

first pattern was a relatively classic one. These were cases where a single HPV type was 

found in the CIN2+ lesion and the same type was found in prior samples. Based on the wellestablished association between persistent infection and development of a high-grade lesion, 

this pattern of detection seemed very clear-cut. Nine cases fell into this category. An 

example is a woman who, after the Month-12 visit, had a punch biopsy triggered by an 

abnormal cytology. The punch biopsy showed HPV 18 in association with a CIN2+ lesion. 

This subject had prior infection with HPV 18 at the Month-6 and Month-12 visit; this is also a 

fairly classic case. 

The second pattern included cases where multiple HPV types were detected in the 

CIN2+ lesion with HPV 16 or 18 infection preceding the development of the lesion. An 

example of that pattern is a subject who had a CIN2+ lesion after the Month-12 visit, with 

HPV 16 and 51 detected. This subject had a number of HPV types detected at previous time 

points, but 16 was detected at the Month-6 and the Month-12 visit, so it was counted as a case 

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77

of HPV-16-associated CIN2+. There were 11 similar cases with multiple types in the lesion 

but a clearer pattern of prior detection of the vaccine type in preceding samples. 

 The third pattern, which was the least common and the most unusual, included cases 

with multiple HPV types in the CIN2+ lesion with no prior detection. There were three such 

cases. The lesions also contained additional non-vaccine types, serotypes that were not 

considered in the analysis, so the question was, which type was the cause of the lesion? 

 Dr. Dubin discussed three cases to show how lesions were assessed. One subject had a 

CIN3 lesion detected by punch biopsy after the Month-12 visit, and HPV 16 and 58 were 

detected in that lesion. That subject subsequently had a LEEP, which confirmed the diagnosis 

of CIN3, but only HPV 58 was detected in the LEEP and at Month 0, Month 6, and Month 12. 

There was no prior detection of HPV 16 in any preceding samples. 

 The second case was a woman who developed a small CIN2 lesion with HPV 18 and 

HPV 58 detected in association with the lesion. A subsequent LEEP was normal, so the 

lesion was removed by the punch biopsy. HPV 58 was detected at entry and at the Month-12 

visit; there was no prior detection of HPV 18. 

 In the third case, the subject had a CIN3 lesion with HPV 16 detected at punch biopsy. 

She subsequently had a LEEP, which showed multiple lesions, each of which had HPV 16. 

HPV 18 was found in a single lesion. Looking back at the history of this patient, multiple 

HPV types were detected, but the only consistent type was HPV 16. There was no prior 

detection of HPV 18. This case would not count as a case of HPV-16-associated CIN2+ in 

the efficacy evaluation because there was prior infection, but it would count as a case of HPV18-associated CIN2+. 

Another analysis was done to evaluate the efficacy of the vaccine against lesions 

considered to be causally associated with HPV 16 or 18. It considered not only the HPV type 

detected in the lesion, but any HPV types found in preceding cytology samples. The use of 

this algorithm was based on the well-established association between persistent oncogenic 

infections and development of CIN2+ lesions. 

 Of the 23 cases detected in the broad analysis, two were in the vaccine group and 21 

were in the control arm, giving a point estimate of vaccine efficacy of 90.4 percent, which 

was highly significant. The majority of these lesions were derived from infections that began 

prior to completion of the three-dose series.

In the three cases where the lesions were not believed to be caused by the types 

detected just in the lesions, two were in the vaccine group and one was in the control arm. 

This left 20 cases: zero in the vaccine group and 20 in the control arm. So in this evaluation, 

vaccine efficacy was 100 percent, which is highly statistically significant. 

 In another analysis, the restriction for subjects to be seronegative for the type 

ultimately found in the lesions was removed. This analysis now considers a broader group of 

individuals, including those who might have been seropositive for HPV 16 to 18 prior to 

vaccination. In the pre-specified analysis, vaccine efficacy was over 90 percent. In the 

analysis that considered not only the DNA detected in the lesion but the prior samples as well, 

the analysis that best reflects lesions likely to be causally associated with HPV 16 and 18, 

vaccine efficacy was 100 percent. Results from an additional analysis, which included 

women who were seropositive for HPV 16/18 prior to vaccination, suggest that vaccine 

efficacy is not likely to be impacted by serostatus prior to vaccination.

 Dr. Dubin then described some efficacy results that looked beyond HPV 16 and 18, 

based on persistent infection endpoints included in the interim analysis. Persistent oncogenic 

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78

infection is well established as a necessary precursor for the development of cervical cancer. 

When multiple types are detected in the lesion, causality must be assessed related to 

individual types. This is likely to be a bigger issue with lesions caused by less frequent types, 

such as 45 and 31, where co-infections are quite common. Persistent infection was used 

because causal association is not an issue when looking at the virus itself and it avoids 

possible confounding effects of multiple types in lesions. 

Given the timing of the interim analysis, most of the persistent infections detected 

began prior to completion of the three-dose series. To assess a 12-month persistent infection, 

a woman would have to be positive at Month 6, Month 12, and Month 18 or Month 12, Month 

18, and Month 24. Very few women had completed the Month-24 visit at the time the interim 

analysis was triggered. Over 90 percent of the 12-month persistent infections were first 

detected at the Month-6 visit, which means they began sometime between Month 0 and 

Month 6. Over 70 percent of the six-month infections began prior to completion of the threedose series. 

 In the Phase II program, there was evidence of cross-protection using an incident 

infection endpoint, and this cross-protection was against types 45 and 31, two types closely 

related to 16 and 18. The interim analysis of the Phase III trial confirmed this effect using a 

more robust endpoint, six-month persistent infection instead of incident infection. So for 

types 35 and 41, statistical significance was achieved using the six-month definition of 

persistent infection. These two types are responsible for about 10 percent of cervical cancers. 

Type 45 is the third most common globally, and 31 is the fourth most common, followed by 

33 and 52. Statistically significant protection was also observed against six-month persistent 

infection with type 52 and it was close for type 33, though not achieved. 

 Another analysis looked at 12-month persistent infections, but because of the lower 

frequency of this endpoint, no assessment could be made on an individual type-specific basis. 

For the 12 oncogenic HPV types, other than 16 and 18, that can be detected with the SPF-10 

system, a point estimate of vaccine efficacy of about 27 percent was observed and was 

statistically significant. 

 Results showing immunogenicity of the vaccine over a five-and-a-half year follow-up 

period have been presented previously. The interim analysis assessed immunogenicity over a 

12-month follow-up period, and found that the vaccine was highly immunogenic for the HPV 

16 and 18 components. Vaccine and immune response were also assessed in subjects who 

were initially seronegative and seropositive for the vaccine types being evaluated. There was 

no real difference in immunogenicity. In fact, when looking at earlier Phase II studies, the 

only difference was that seropositives achieve a higher immune response earlier, but the 

plateau is essentially the same regardless of serostatus. 

 Lastly, Dr. Dubin covered some of the safety evaluations. There was a very high level 

of compliance with completion of study visits and it was comparable between the two groups. 

There were very few dropouts related to adverse events, and this was also well balanced 

between the treatment groups. There was no difference in the number of events that led to 

dropout, and there were many other reasons for subjects dropping out of the study, mostly 

migration from the study area. 

Adverse events reported during a 30-day period following each dose of vaccine were 

categorized as local injection-site symptoms, general symptoms, and combined symptoms. 

The vaccine induced a somewhat higher rate of local injection-site symptoms -- pain, redness, 

and swelling -- compared to the control used. General symptoms were more comparable 

This document has been archived for historical purposes.
79

between the two groups, with slightly higher rates in the HPV group compared to the control. 

There was no increase in local or general symptoms with subsequent doses, and the majority 

of these reports were low-grade and transient events. 

The reactogenicity profile of the vaccine did not result in any differential compliance 

with receipt of the second and the third dose, which indicates that the vaccine is well tolerated 

from the perspective of the subject. All events following each dose of vaccine were stratified 

by initial serostatus or DNA status and no differences were seen in the reactogenicity pattern, 

depending on whether subjects were naïve to the vaccine types, seropositive, or DNA positive 

to one or both of the vaccine types. The safety profile appeared to be quite comparable. 

 Another analysis considered less frequent events. Data on symptoms were solicited 

very proactively for the 30-day period following each of the three doses. Medically 

significant events, defined as conditions that prompted an emergency room visit or a 

physician intervention, new onset of chronic diseases and new onset of autoimmune diseases, 

were actively solicited throughout the entire duration of the trial. There was no difference in 

the proportion of subjects reporting any of these events. Serious adverse events were reported 

over the duration of the trial without any time restriction; both the proportion of subjects 

reporting serious adverse events and the number of serious adverse events reported were quite 

similar in the two groups. 

Pregnancy outcomes were assessed as one of the important safety measures, even 

though there were contraindications to pregnancy in the vaccination phase of the protocol. 

The rate of specific pregnancy outcomes was well balanced between the two groups. 

 This is the largest vaccine study conducted to date and it has helped to characterize the 

natural history of HPV in association with multiple types detected in lesions. With the 

methodology that will be used to look at lesions that develop in vaccinated women in a postlicensure setting, this will be important in trying to better understand causal association with 

vaccine and non-vaccine types. 

 This study has confirmed a high level of protection against HPV 16 and 18 CIN2+ 

lesions in a broadly defined cohort of women. The vaccine efficacy estimate is 90 percent 

considering any CIN2+ lesions with HPV 16 or 18 detected and 100 percent against lesions 

where HPV 16 and 18 were likely to be causally associated with the lesion. There was a high 

level of vaccine efficacy regardless of initial HPV 16/18 serostatus, which will be important 

as use of the vaccine is considered for non-naïve women. The majority of endpoints were 

derived from infections detected prior to completion of the three-dose series, which suggests 

that the onset of vaccine effect may actually begin prior to completion of the full three-dose 

series. 

The HPV-008 study extends some previous preliminary evidence of cross-protection. 

There is evidence of efficacy against HPV 45, 31, and 52, using a six-month persistent 

infection endpoint. Efficacy is also seen against 12-month persistent infection in an analysis 

that considers a combination of 12 non-vaccine types. Persistent infection is an important 

endpoint in assessing these other types because the analysis is not confounded by the potential 

for multiple types detected in biopsies. Finally, the study confirmed that the vaccine is highly 

immunogenic and generally well tolerated. 

HPV Vaccines: Future Recommendation Considerations

Dr. Markowitz provided information on distribution, post-licensure monitoring, and 

state legislative action, as well as the next issues for the ACIP consideration related to HPV 

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80

vaccine. The ACIP made its recommendations a year ago, followed by a VFC vote, 

recommendations on the Web in July and the VFC contract in October. The vaccine was 

included in the National Injury Compensation Program in February, and the ACIP statement 

was published in March. Through March of 2007, about 5 million doses have been 

distributed, 49 percent of that through the CDC contract and 51 percent non-CDC. By April 

2007, all states had purchased vaccine for the public sector. 

 Monitoring includes post-licensure safety monitoring, vaccine coverage, and disease 

impact. Merck has an extensive post-licensure safety program as part of their agreement. 

They will be doing a post-marketing study in a managed-care organization. They also have a 

vaccine pregnancy registry in which about 300 women have been enrolled. That annual 

report will be analyzed and could be presented to ACIP at a later date. A variety of safety 

studies are ongoing through the Nordic cancer registry and those could also be presented. 

Regarding coverage, a variety of data will be available. Some are in the traditional 

vaccine coverage surveys, but information on HPV vaccine has also been included in other 

national surveys and those data will become available. The teen module of the National 

Immunization Survey was conducted in the fourth quarter of 2006 and will be repeated in the 

fourth quarter of 2007. This is a random-digit dialing telephone survey of parents, with 

provider check for verification of immunizations. Funding was just received to expand this in 

2008 to provide state-specific estimates. The adult module is being conducted now (May 

through August), and the first data will be available in the fourth quarter of 2007. That is also 

a telephone interview, but with no provider check for verification of immunization status. 

The National Survey of Children's Health, which is ongoing, will provide national as well as 

state-based estimates. There are about 92,000 children in that sample and data are based on 

parental recall only. 

 There has been substantial media attention around HPV vaccine legislation. As of 

June 2007, legislation has been introduced in 41 states, and in 11 states bills have been signed 

into law. The vast majority of these laws are about education related to HPV and HPV 

vaccine; some are related to funding and insurance to cover HPV vaccine. Twenty-four 

states have introduced legislation specifically to mandate HPV vaccine for school entry. In 

Texas, there was an executive order for a middle-school vaccination requirement, which was 

overridden by the legislature. In Virginia a mandate did pass that requires HPV vaccine for 

girls entering grade six, but there are very broad exemptions. In North Dakota and New 

Hampshire, legislation has been passed to allocate funds to provide vaccines at no cost to 

females 11 to 18 years of age. 

 There are four major upcoming issues for ACIP: considerations regarding the bivalent 

HPV vaccine; issues related to having two HPV vaccines on the market; additional data from 

the quadrivalent and bivalent vaccine trials that may impact recommendations in the coming 

years; and considerations that were not included in the first ACIP statement. 

 Information about the bivalent vaccine was presented earlier. The BLA submitted to 

FDA in March of 2007 included data on females 10 to 55 years of age. The FDA decision 

would be in January 2008 at the earliest. If the vaccine receives an indication for currently 

recommended age groups, the work group and ACIP will need to review the clinical trial data 

on efficacy, immunogenicity, and safety, as well as additional information on adjuvants, since 

this is a new adjuvant. If there are indications for use in older women, the committee will 

have to consider recommendations for those age groups. Options include permissive, riskbased, no recommendation, or some other recommendation. Data on sexual behavior in the 

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81

U.S. will be reviewed, from national surveys, natural history, and HPV incidence data in older 

women as well as other information on HPV and cost-effectiveness in this older age group. 

 With two HPV vaccines on the market, there will be considerations and data needs 

around the issues of preference and interchangeability. The work group has started examining 

whether there are differences related to protection against HPV 16 or 18 and cervical cancer 

between the two vaccines, or differences related to duration of protection, immunogenicity, or 

cross-protection. There are differences related to protection against HPV 6 and 11 related 

diseases since these types are included in the quadrivalent vaccine and not in the bivalent 

vaccine. Another issue will be cost-effectiveness. Any precedent for how ACIP has dealt 

with the preference when making recommendations for other vaccines will be reviewed. 

There has been no situation completely analogous to HPV vaccine that ACIP has had to 

consider. 

If there is no preference, there will be issues around interchangeability of doses. At the 

time of licensure, there will be no data on interchangeability. If someone starts the series with 

one vaccine, the quadrivalent, for example, can she complete her doses with the bivalent 

vaccine? 

 In terms of additional data, both manufacturers are looking at efficacy in females older 

than 25 or 26; safety and immunogenicity; co-administration with adolescent vaccines; safety 

and immunogenicity in HIV-positive women and, from Merck, HIV-positive men. Efficacy 

trials in men are being conducted for the quadrivalent vaccine, and both manufacturers are 

doing Phase IV and long-term follow-up studies. 

On-going studies with the quadrivalent vaccine could impact recommendations. The 

efficacy trial in women 24 to 45 years of age is looking at prevention of persistent infection 

and disease in this older age group of women. There are also two studies in men; the earliest 

data would be available in the third quarter of 2008. If FDA or ACIP require efficacy data 

instead of immunogenicity data to consider recommendations in older women, 2008 would be 

the time frame, and for recommendations in males, it would be 2009 or 2010. This depends 

on when the endpoints occur because these are endpoint-driven analyses. 

Some issues have come up about considerations not included in the current statement, 

such as inadvertent administration of the vaccine by the subcutaneous route or other special 

situations related to pre-existing disease in women.

 Finally, the ACIP work group has talked about ACIP statements for HPV vaccine, 

including format. The preference was a new ACIP statement with information on both 

vaccines, rather than a separate statement for the bivalent vaccine. The time line for a new 

draft statement would probably be February 2008. 

 Future plans for ACIP meetings include further review of Phase III data, a discussion 

of the adjuvant, and an update on any new data from the quadrivalent HPV vaccine in 

October. Epidemiology of HPV and various HPV-related outcomes should be addressed, 

including genital warts and RRP, followed by discussion of potential recommendations. 

February would be the earliest there could be a vote. At that time, cost-effectiveness data 

would be reviewed as well. 

Discussion

 Dr. Gilsdorf asked about the tissue samples obtained by punch biopsy, cone, or LEEP, 

and whether the virus was detected by PCR only or also confirmed by tissue probes. Dr. 

Dubin replied that the protocol was to do microdissection of the lesion and then apply PCR on 

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82

samples derived from the lesion. One of the ways this is being assessed now is to look at 

assays that allow evaluation of gene expression in these cases. The assay currently being used 

has type specificity for expression of the E-4 protein. Analyses done with the E-4 protein 

immunohistochemical assay fully support the causal associations made in the study. 

 Dr. Gilsdorf asked whether the histochemical data confirmed the PCR data. Dr. Dubin 

replied that the study specifically looked at lesions where HPV 16 or 18 was detected only in 

the lesion but not in any prior samples. The available immunohistochemical probes are for 

HPV 16 and 18, and those were not detected in the lesions. In other lesions where the vaccine 

type detected in the lesion and in the prior cytology samples were known, the E-4 

immunohistochemical signal was consistently detected in the lesions. 

 Dr. Chen commented that it is challenging to sort through a large number of individual 

HPV VAERS reports with multiple adverse events when the staff is limited. At one point, a 

panel of data safety monitoring tools was developed to look for new permutations of new 

adverse events or new syndromes. He asked whether these tools were being applied to HPV. 

Dr. Iskander responded that Dr. Chen was referring to advanced signal-detection techniques 

or data mining, as a way of sorting through very large and complicated databases. A 

conscious decision was made not to present that type of data to the ACIP without sufficient 

background, but in fact steps are being taken to use both types of analyses. They are routinely 

used in joint analyses of VAERS done with FDA and incorporated into publications. Some of 

those methods will be brought before the committee in the future, first in terms of general 

background and then incorporated routinely in some of the safety analyses. 

 Dr. Abramson asked whether there was any plan to look at the effect of the new 

mandate in Virginia, in terms of increasing immunization and opt-out categories. Dr. 

Markowitz replied that there was an adolescent work group at CDC and the issue has been 

discussed with the Immunization Services Division. There is also the interesting case of New 

Hampshire and other states that have made vaccine available free of charge. CDC is actively 

discussing how to evaluate those states that have adopted either legislation or other 

implementation measures. 

 Dr. Schuchat commented that there was now an opportunity to pitch state-specific 

estimates for adolescent coverage through a teen module at the NIS. There will be an ongoing examination of attitudes about vaccine acceptance in the NIS and also in insurance 

modules. The plan is also to collect ongoing information about coverage, acceptability or 

safety concerns, and financial patterns. 

 

UPDATE: VARICELLA

Adriana Lopez, CDC/NCIRD/DVD

 

Ms. Lopez presented results from an investigation of an outbreak of varicella among 

two-dose recipients. In the past two years, ACIP has made new recommendations for 

varicella immunization. In June 2005, a second dose of varicella vaccine was recommended 

in children for outbreak control, resources permitting. Then in June of 2006, a routine second 

dose for all children was recommended, with the first dose given to children 12 to 15 months 

of age, the second dose for children four to six years of age, and catch-up vaccination for all 

persons over age six. 

 During the fall of 2006, an outbreak of varicella occurred in southeast Arkansas. 

When the outbreak came to the attention of the health department, 31 cases had been reported. 

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83

Of these, eight were among two-dose recipients, and all cases were reportedly mild. The 

outbreak occurred in an elementary school complex that housed three schools. School A 

included pre-K students, School B included grades K through three, and School C included 

grades four through six. The same school complex had experienced an outbreak during 

January and February of 2006. During that outbreak, in accordance with the June 2005 ACIP 

recommendation, the Arkansas health department set up a vaccination clinic to help with 

outbreak control. Approximately 400 students were vaccinated at that time, and many 

received a second dose. 

Because cases in this current outbreak included two-dose recipients, CDC was invited 

to assist with the investigation. The main objectives of the investigation were to confirm 

varicella in cases that had received two doses and to characterize the vaccine effectiveness 

among one- and two-dose recipients, if possible. 

 A case was defined using the Council of State and Territorial Epidemiologists case 

definition of acute maculopapular vesicular rash without other apparent cause occurring 

between September 1 and December 18 among students in the school complex. Disease in 

vaccinated persons is generally mild with fewer than 50 lesions, shorter duration of illness, 

and atypical appearance with macules and papules and few or no vesicles. Given the large 

number of insect bites common to this area, a person had to have at least three lesions to be 

considered a case. Laboratory confirmation of cases was done using PCR to test lesion 

specimens and environmental samples and IgM for blood and saliva specimens. 

 Cases among students in the school complex were identified from the health unit, the 

school nurse, and a survey that was sent to the entire school. The survey included questions 

about vaccination status and varicella disease history, medical conditions, and screening 

questions for rash illness to try to identify mild cases. Parents of case-patients were contacted 

and asked about clinical information, medical conditions that could affect immunity, and 

medication. 

Varicella vaccination status was verified by reviewing the Arkansas immunization 

registry. Alternate sources included paper records at the local county health department and 

the parental surveys, if the parent had provided date of vaccination. Children were considered 

unvaccinated if they had received their first dose less than or equal to 42 days before rash 

onset. Children receiving their second dose less than or equal to 42 days before rash onset 

were considered as having indeterminate vaccination status. 

 The overall response rate from the school-wide survey was 79 percent, with the 

response from School C being significantly lower than responses from Schools A and B. No 

differences were identified between responders and non-responders with respect to gender and 

vaccination status. However, a difference was found for race/ethnicity, where AfricanAmerican children were less likely to respond compared to white or Hispanic children. 

 A total of 85 cases were identified during the outbreak, which lasted almost four 

months. Most cases occurred among one-dose recipients, but two-dose recipient cases 

occurred throughout the entire outbreak. None of the cases had more than 250 lesions. The 

two-dose cases tended to be slightly milder than the one-dose cases and those with previous 

disease, although the difference was not statistically significant. Those with unknown number 

of lesions were excluded from this analysis. Similarly, no statistically significant differences 

were seen between the one- and two-dose cases and those with prior disease history with 

respect to rash description, median duration of rash, and fever. However, two-dose cases and 

those with prior disease tended to have shorter rash duration than one-dose cases, four and six 

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84

days, respectively. 

 The mild clinical presentation of cases during this outbreak made diagnosis difficult. 

Clinical specimens from a lesion and saliva were collected on the day of rash onset. Twentyfive (29 percent) of the cases were among two-dose vaccine recipients, with three of them 

having either previous or unknown history of disease, for an attack rate of 10.4 percent. A 

majority (64 percent) of the cases occurred among one-dose vaccine recipients. Seven of 

these had previous history of disease, for an attack rate of 14.6 percent. Lastly, six cases (7 

percent) had no history of vaccination, but all had previous history of disease. Thus, it was 

not possible to calculate an attack rate or vaccine effectiveness against no vaccination. 

 The overall vaccination coverage with at least one dose in the school complex was 97 

percent, and the two-dose coverage was 41 percent. Twenty-seven cases had specimens 

collected for laboratory confirmation. Six of those had positive results; five specimens were 

from lesions and positive by PCR; one from a two-dose recipient, three from one-dose 

recipients, and one from an unvaccinated person with history of disease. The sixth positive 

result was from IgM from a one-dose recipient.

 Environmental samples collected from the school, and bedding and bedclothes from 

cases were also tested. A set of pajamas from a case with indeterminate vaccination status 

was PCR positive. This case also had a positive lesion specimen. A pillowcase from a onedose recipient was also PCR positive. This case did not have clinical specimens for testing. 

 Because there were no cases in persons with no vaccination and no disease history, 

vaccine effectiveness was calculated against clinical varicella using historic attack rates. An 

attack rate for unvaccinated of 80 percent was used. The vaccine effectiveness among two 

doses versus unvaccinated for this outbreak was 87 percent, with 95 percent confidence 

intervals of 80.5 to 91.4. The one-dose versus unvaccinated vaccine effectiveness was 81.8 

percent with 95 percent confidence intervals from 75.8 to 86.2 percent. Although the twodose vaccine effectiveness point estimate was higher than the one-dose estimate, the 

confidence intervals overlap. 

Some limitations to this investigation included that there may not have been sufficient 

power to detect differences between the one- and two-dose cases. Misclassification of cases 

could have occurred because of the broad clinical definition used, which could have led to 

false positives. Similarly, mild disease could have led to false negatives. Lesion-based 

laboratory diagnostics were only helpful while transient rash was still present; it was not 

possible to confirm any of the cases reported before CDC's arrival. Misclassification of 

disease history could have occurred because this was based mainly on parental report. 

Response rate was significantly lower among students from School C, however since 

vaccination status was obtained from the state registry, this is unlikely to have affected 

vaccination coverage and effectiveness estimates. 

 This was one of the largest varicella outbreaks investigated in recent years, and the 

first U.S. outbreak reported with a significant number of two-dose vaccine recipients. 

Challenges with case ascertainment, because of the mild presentation of disease, may 

preclude the evaluation of two- versus one-dose risk-reduction assessments in outbreak 

settings. Moderate two-dose coverage of 40 percent was insufficient to prevent this outbreak. 

Additional vaccine-effectiveness studies for two doses are needed. Lastly, to assess the 

impact of the routine two-dose varicella vaccination policy, it will be important to monitor the 

number and size of outbreaks as a key outcome. 

 

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85

Discussion 

 Dr. Gilsdorf asked whether the two-dose failures all received their vaccine from the 

same provider and if so, how about vaccine storage. Ms. Lopez replied that they all received 

their vaccine at the clinic held in February of 2006. Handling and storage were evaluated and 

everything looked fine. 

Dr. Katz asked why pillowcases and pajamas were cultured. Ms. Lopez replied that 

they were trying to see if environmental sampling would be a good way to diagnose varicella 

in outbreaks where CDC comes in after the fact. Dr. Katz asked if there were any data from 

past environmental sampling of varicella and Ms. Lopez replied that environmental sampling 

had been done during an outbreak in a West Virginia long-term care facility. The index case 

was a zoster case, and there were three varicella cases that occurred subsequent to that zoster 

case. Environmental sampling made it possible to link the cases, which all had a unique strain 

of varicella. 

Dr. Iskander shared a recent observation from VAERS on reports of multiple, small 

clusters following second doses of varicella vaccine described as “cellulitis”. They do not 

appear to be clustering and may represent provider unfamiliarity with the normal safety 

profile of the vaccine. The other possibility is that there may be a biologic difference in the 

reactogenicity of second dose depending on the age at which it is given. Pictures or any other 

information are being sought that might shed additional light on this emerging clinical 

observation. 

AGENCY UPDATES

CDC

Dr. Schuchat reported that the reorganization of the Coordinating Center for 

Infectious Diseases at CDC was approved in March, so the National Center for Immunization 

and Respiratory Diseases now has official status. There is an annual report and a new web 

site, including a vaccine component. There is also a new module for adolescent immunization 

coverage. An adolescent immunization campaign will be launched this summer, targeted to 

parents of 11- to 12-year-old children. 

CMS

Ms. Murphy mentioned the VFC maximum administration rates and the fact that she 

had been receiving many inquiries. She explained that she is the immunization focal point for 

Medicaid, but Medicare and Medicaid are not related and do not always share information, so 

she would appreciate being kept in the loop. She formulates answers to letters that come to 

her. Because of the publicity that the low VFC administration rates have been getting lately, 

the stock answer has been, "I can't do a thing about it. It's all in regulation. It's all in statute." 

If the VFC maximum regional administration rate is to be changed, states must demonstrate 

that this needs to be done. When the discussion started in 2005, she discovered that only five 

states were actually paying the maximum rate for Medicaid. Since she has been working with 

agencies and associations to work with Medicaid and individual states, there are now nine 

states paying the maximum rate for Medicaid and 12 other states have raised their rates. She 

urged the committee to continue working with the state Medicaid agencies and immunization 

program agencies to have rates raised to the maximum. If that can be done, Ms. Murphy can 

then work with the different associations to ensure that studies are undertaken in order to 

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86

show what is needed to obtain a more equitable rate. 

DOD

Dr. Cieslak first addressed the issue of smallpox vaccine and contact vaccinia in 

vaccine recipients. After vaccinating for exactly five years with well over a million 

recipients, there have been 60 cases, which is an average of one case a month over the life of 

the DOD's resumption of smallpox vaccination. In March of this year, there were five cases, 

but that is probably just a statistical aberration. All of the vaccine is coming from the same lot 

and the five cases were widely dispersed geographically. 

 The second issue involved the adenovirus vaccine. The DOD is engaged in a study of 

a new bivalent adenovirus vaccine involving Serotypes 4 and 7, which are historically the 

types that have caused most severe adenoviral disease amongst military recruits. There is 

currently an outbreak of severe adenoviral-14 disease among Air Force basic trainees at 

Lackland Air Force Base in San Antonio. The long-term implications are being studied, i.e., 

whether this is an aberration or here to stay. The DOD is also interested in whether the 

bivalent 4/7 vaccine will provide any cross-protection against serotype 14 or whether a type14 serotype might have to be added to a vaccine construct. 

 

FDA 

Dr. Houn reminded the audience that the sanofi pasteur H5N1 influenza virus vaccine 

was approved in April. In May, the final guidance on development of both seasonal and 

pandemic influenza virus vaccines was issued. At the May VRBPAC meeting, FluMist was 

discussed, as well as the Acambis smallpox vaccine, which was voted by the VRBPAC to be 

the first vaccine to have a recommendation for a medication guide. This is an FDA-approved 

patient package insert on risks and benefits. It was also recommended to have a riskminimization action plan to minimize identified risks of that vaccine. 

HRSA 

Dr. Jevaji reported that the vaccine autism trial started on June 11th and concluded on 

June 26th. Three special masters heard the evidence on a test case. The test case was 

determined by the petitioners, and then petitioners and respondents introduced testimony for 

the general population, as well a specific causation related to the test case. 

 The inquiries involved a theory that MMR vaccine and thimerosal-containing vaccines 

can cause the alleged injury. So far, 5100 thimerosal-related autism claims have been filed 

with the National Vaccine Injury Compensation Program, and of these, 4800 cases are 

pending. The remaining 300 were either dismissed because of the statute of limitations or 

they chose to go to the regular program. Since both parties responded and the petitioners 

consented, the hearing can be accessed online by searching on the web for "autism and court 

hearing." Future hearings regarding the autism trial will be heard on two theories; designation 

of the test cases will be determined by the Court and the special masters. 

 On February 7th, Representative Dave Weldon, a Republican from Florida, and 

Carolyn Maloney, a Democrat from New York, introduced a bill called the Mercury-Free 

Vaccines Act of 2007. This bill was introduced to amend the FDA act to eliminate mercury 

exposure from the vaccines. The bill was referred to the Committee on Energy and 

Commerce. 

 On April 20th, the Federal Register notice was published announcing the addition of 

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87

the meningococcal and HPV vaccines to the list of vaccines covered by the National Vaccine 

Injury Program. 

The Statute of Repose for influenza vaccine is coming to an end on June 30, 2007. So 

far, there have been 117 claims, of which 106 represented adults and the rest were children 

under the age of 18 years. The Statute of Repose is a look-back provision that goes back eight 

years from the date the vaccine came onto the table. 

 

NIH 

Dr. Curlin announced that the Jordan Report had finally been delivered, on the last 

day of the ACIP meeting. It can be downloaded or one can get hard copies by emailing 

Barbara Mulach at NIH. 

NVPO 

Dr. Gellin announced that Angela Shen would be returning from maternity leave after 

Labor Day and that Dan Salmon was returning to NVPO to focus on vaccine safety. The 

national vaccine plan is in need of an update and more will be said about that in the future. 

The adolescent working group has a paper in the process of being submitted that highlights 

the challenges of adolescent vaccination. 

Dr. Hinman provided information about the NVAC registries. The immunization 

coverage subcommittee of NVAC has led the development of a progress report on 

immunization and information systems or immunization registries. This was approved in 

February of this year by NVAC and should be posted on the Web in October or November, 

and we hope that it will be published. 

NVAC’s target is 95 percent of children less than six years of age having two or more 

immunizations recorded in an immunization registry by the year 2010. As of the end of 2005, 

it was at 56 percent and at the end of 2006, it appeared to be about 65 percent. 

Registries are the most developed of the public health information systems and, 

perhaps, the only ones that really cross the public sector/private sector divide. They provide 

clinical-decision support to providers in states around the country. They are increasingly 

containing information about adults and the majority of registries accept information on all 

ages. The majority of pandemic influenza plans incorporate the use of registries to track 

immunizations given during pandemic response. The next step is linking with electronic 

health records, which is already being done in a limited number of places. Some of the major 

barriers have to do with exchanging information across state lines, which currently requires 

setting up individual memoranda of agreement. Providing long-term financial sustainability 

for registries continues to be a problem, but progress is being made. 

PUBLIC COMMENT

 

Mr. Scott Lassiter said he believed the CDC had misled the ACIP on thimerosal and 

that the five oft-quoted epidemiologic studies weren't worth the paper they're written on. At 

the request of Congress last year, the NIH convened a panel of the top epidemiologists in the 

country who concluded that the Verstraaten study had several serious flaws and that the other 

studies were even worse. The panel concluded it was still an open question whether vaccines 

cause autism. 

This document has been archived for historical purposes.
88

 According to Mr. Lassiter, internal correspondence obtained by the Freedom of 

Information Act indicates that the CDC knowingly manipulated data that originally showed a 

connection between thimerosal and autism. For proof, he suggested reading the web site 

putchildrenfirst.org, or reviewing the CDC's own e-mails and meeting minutes from that time 

period. The hard science in lab and animal research from leading universities indicates that 

thimerosal is a dangerous neurotoxin, twice as potent as methylmercury, and that it causes 

autism-like behaviors and white-matter changes in the brain. He reminded the committee of 

its responsibility to put children first and urged members to do their own research. 

Karen Beauvais spoke on behalf of the National Autism Association of the greater 

Atlanta area, consumers of vaccines, and a seven-year-old boy named Joshua Beauvais who 

received 277 times over the EPA-allowable amount of thimerosal in his infant vaccines. 

Joshua has undergone four years of very aggressive chelation therapy. He was endoscopied 

and not found to have the typical autism-measles hyperplasia, which led to extensive 

industrial testing of urinary porphyrins. Joshua is showing hundreds of times over what he 

should have for mercury in his body, all of which is believed to have been from his Hib, his 

DTaP, and his hep-B series. 

She read the following from the material data safety sheet for thimerosal, which is still 

in influenza vaccine and other vaccines: "This substance may be toxic to the kidneys, the 

liver, the spleen, bone marrow, and the central nervous system. Repeated or prolonged 

exposure to the substance can produce target organ damage. Repeated exposure to highly 

toxic material may produce a general deterioration of the health by accumulation in one or 

many of the organs." 

 The work of Amy Tsao indicates that children have sustained DNA damage, and the 

material data safety sheet indicates that new genetic defects are being seen in humans with 

thimerosal. She implored the committee to make vaccines safe for all: for pregnant women 

and for little children. 

 

 As there was no further public comment, the meeting was adjourned at approximately 

1:33 p.m. 

I hereby certify that to the best of my 

knowledge, the foregoing Minutes of the 

June 27-28, 2007 ACIP Meeting are 

accurate and complete.

 ______________________ 

_________________________________ 

Date Jon S. Abramson, M.D., Chair, 

Advisory Committee on Immunization 

Practices

This document has been archived for historical purposes.
89

Attachment One: List of committee members and liaison members and other attendees

CHAIR

JON S. ABRAMSON, M.D.

Weston M. Kelsey Professor and Chair, 

Department of Pediatrics

Wake Forest University School of Medicine, 

Winston-Salem, North Carolina

EXECUTIVE SECRETARY

LARRY K. PICKERING, M.D.

Senior Advisor to the Director, National 

Immunization Program 

Centers for Disease Control and Prevention, 

Atlanta, Georgia

 

ACIP MEMBERS

BAN MISHU ALLOS, M.D.

Assistant Professor, Division of Infectious 

Diseases

Vanderbilt University School of Medicine, 

Nashville, Tennessee

CAROL BAKER, M.D.

Professor of Pediatrics, Molecular Virology and 

Microbiology

Baylor College of Medicine, Houston, Texas

MR. ROB BECK

Palmyra, Virginia

JANET R. GILSDORF, M.D.

Director, Pediatric Infectious Diseases, 

Department of Pediatrics and Communicable 

Diseases

University of Michigan, Ann Arbor, Michigan

HARRY HULL, M.D.

State Epidemiologist and Director

Minnesota Department of Health, Minneapolis, 

Minnesota

SUSAN LETT, M.D., M.P.H.

Medical Director, Massachusetts Department of 

Public Health

Jamaica Plain, Massachusetts

TRACY LIEU, M.D.

Associate Professor of Ambulatory Care and 

Prevention

Harvard Pilgrim Healthcare and Harvard 

Medical School, Boston, Massachusetts

JULIE MORITA, M.D.

Medical Director, Immunization Program

Chicago Department of Health, Chicago, Illinois

DALE L. MORSE, M.D.

Director, Office of Science and Public Health

New York State Department of Health, Albany, 

New York

KATHLEEN NEUZIL, M.D., M.P.H.

Clinical Associate Professor of Medicine

University of Washington, Seattle, Washington 

PATRICIA STINCHFIELD, NP

Director, Pediatric Infectious Disease and 

Immunology

Children's Hospitals and Clinics of Minnesota, 

St. Paul, Minnesota 

CIRO VINCENT SUMAYA, M.D., M.P.H.

School of Rural Public Health

Texas A&M University System Health Science 

Center, College Station, Texas

JOHN J. TREANOR, M.D.

Associate Professor of Medicine

University of Rochester, Rochester, New York

EX OFFICIO MEMBERS

NORMAN BAYLOR, Ph.D.

Food and Drug Administration, Rockville, 

Maryland

JAMES E. CHEEK, M.D.

National Epidemiology Program, Indian Health 

Program, Albuquerque, New Mexico

GEORGE CURLIN

Medical Director, National Institutes of Health, 

Bethesda, Maryland

BRUCE GELLIN, M.D.

Director, National Vaccine Program Office, 

Washington, D.C.

WAYNE HACHEY, DO, M.P.H.

Department of Defense, Falls Church, Virginia

INDIRA JEVAJI, M.D.

Medical Officer, Division of Vaccine Injury 

Compensation

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HRSA, Bureau of Health Professions, Rockville, 

Maryland

LINDA MURPHY

Centers for Medicare and Medicaid Services, 

Baltimore, Maryland

KRISTIN NICHOL, M.D. 

Chief of Medicine, VA Medical Center, 

Minneapolis, Minnesota

LIAISON REPRESENTATIVES

American Academy of Family Physicians

DOUG CAMPOS-OUTCALT, M.D.

University of Arizona, College of Medicine, 

Phoenix, Arizona

JONATHAN TEMTE, M.D.

Family Practice Residency Program, Madison, 

Wisconsin

American Academy of Pediatrics

JOSPEH A. BOCCHINI, JR., M.D.

Children's Hospital of LSU, Shreveport, 

Louisiana

America's Health Insurance Plans

TAMARA LEWIS, M.D., M.P.H.

Medical Director, Intermountain Healthcare, Salt 

Lake City, Utah

American College Health Association

JAMES C. TURNER, M.D.

Director, Elson Student Health Center

University of Virginia, Charlottesville, Virginia

American College of Physicians

SANDY FRYHOFER

American Medical Association

LITJEN TAN, Ph.D.

Director, Infectious Diseases, Immunology, & 

Molecular Medicine

Chicago, Illinois

American Osteopathic Association

STANLEY E. GROGG, D.O.

Oklahoma State University, Tulsa, Oklahoma

American Pharmacists Association

STEPHAN L. FOSTER, Pharm.D.

University of Tennessee, Memphis, Tennessee

Association of Teachers of Preventive Medicine

W. PAUL MCKINNEY, M.D.

Professor and Chief, Division of Internal 

Medicine

University of Louisville, Louisville, Kentucky

Biotechnology Industry Organization

CLEMENT LEWIN, Ph.D., MBA

Executive Director for Strategic Planning & 

Intelligence

Chiron Vaccines, Orange, Connecticut

Canadian National Advisory Committee on 

Immunization

DR. JOANNE LANGLEY, Division of 

Infectious Diseases, Department of Pediatrics, 

Canadian Center for Vaccinology, Dalhousie 

University, Nova Scotia, Canada

Healthcare Infection Control Practices Advisory 

Committee

STEVE GORDON, M.D.

Cleveland Clinic, Cleveland, Ohio

Infectious Diseases Society of America

SAM KATZ, M.D. 

Wilbert C. Davison Professor 

Duke University Medical Center, Durham, North 

Carolina

London Department of Health

DAVID M. SALISBURY, M.D.

Director of Immunization, Department of Health. 

London, UK

National Association of County and City Health 

Officials 

NANCY BENNETT, M.D. 

Director, Center for Community Health

University of Rochester School of Medicine and 

Dentistry, Rochester, New York

JEFFREY DUCHIN, M.D.

Chief, Communicable Disease Control, Seattle, 

Washington

National Foundation for Infectious Diseases

WILLIAM SCHAFFNER, M.D.

Professor and Chairman, Vanderbilt University 

School of Medicine

Nashville, Tennessee

National Immunization Council and Child 

Health Program, Mexico

VESTA RICHARDSON, M.D.

General Director, National Center for Health and 

Infancy and Adolescence

Colonia Merced Gomez, Mexico

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National Medical Association

WINSTON PRICE, M.D.

National Vaccine Advisory Committee

GARY FREED, N.D., M.P.H.

Division of General Pediatrics, University of 

Michigan, Ann Arbor, Michigan

Pharmaceutical Research and Manufacturers of 

America

DAMIAN A. BRAGA

President, sanofi pasteur - U.S., Swiftwater, 

Pennsylvania

PETER PARADISO, M.D.

Vice President, Wyeth Vaccines, Collegeville, 

Pennsylvania

Society for Adolescent Medicine

AMY B. MIDDLEMAN, M.D., M.P.H. 

Baylor College of Medicine, Texas Children's 

Hospital, Houston, Texas

Society for Healthcare Epidemiology of America

HARRY L. KEYSERLING, M.D.

Professor of Pediatrics, Emory University, 

Atlanta, Georgia

Other Registered Attendees

Peter Alberti, Merck & Co.

Christopher Ambrose, Medimmune, Inc.

Dilek Arman, GAZI University, Turkey

Judith Armoni, sanofi pasteur

Jennifer Armstrong, GlaxoSmithKline

Phyllis Arthur, Merck & Co.

Kevin Ault, Merck Vaccine Division

Mutlu Aydingulu, sanofi pasteur, Turkey

Lynn Bahta, Minnesota Department of Health

Yaela Baine, GSK Biologicals

Allyn Bandell, Medimmune

Robert Bargatze, LigoCyte Pharmaceuticals, Inc.

Eliav Barr, Merck & Co., Inc.

Kenneth Barr, National Vaccine Program Office

Joan Benson, Merck & Co., Inc.

Eugenia Barnard, Parent

Guthrie Birkhead, New York State Department 

of Health

Andrew Bowser, AB Writing & Editing, Inc.

Lynn Bozof, National Meningitis Association

Kimberly Bradley, Merck & Co., Inc.

Esthel Brakel, GlaxoSmithKline, Belgium

Dennis Brooks, Merck & Co., Inc.

Ariel Buda-Levin, SciMed

Delvin Carmel, Wyeth

Donna Cary, sanofi pasteur

Danielle Castellani, Cooney/Waters Group

Dan Pharm Casto, Merck Vaccine Division

Michael Chaney, GA Chapter, AAP

Richard Clover, University of Louisville

Kathleen Coelingh, Medimmune Vaccines

Chis Colwell, Biotechnology Industry 

Organization

Edward Conner, Medimmune

Lenore Cooney, Cooney/Waters Group

Steinhart Corklin, Merck & Co., Inc.

Mike Corvaia, Balance Medical Staffing

Margaret Cross, Palo Alto Medical Foundation

Christensen Cuculich, Wyeth Pharmaceuticals

Gerard Cunningham, Merck & Co., Inc.

Stephen Dachowski, Merck Vaccine Division

Donald Dalrymple, Dalrymple & Associates, 

LLC

Adrian Dana, Merck & Co., Inc.

Ana Dayton, Constella Group

Michael Decker, sanofi pasteur

Shelley Deeks, Public Health 

Agency/Immunization and Respiratory 

Infections Division

Laurence N. DeMoer, GlaxoSmithKline, 

Belgium

Liad Diamond, GSK Biologicals

Richard Dinovitz, Wyeth Pharmaceuticals

Jagdeep Dosanjh, GlaxoSmithKline

Kelley Doughtery, Merck & Co., Inc.

Gary Dubin, GlaxoSmithKline

Colleen Duffy, Merck Vaccine Division

Frank Dutko, Merck & Co., Inc.

Sal Espinosa, Merck & Co., Inc.

Geoffrey Evans, Division of Vaccine Injury 

Compensation/HRSA

Lievano Fabio, Merck & Co., Inc.

Mark Feinberg, Merck & Co., Inc.

Gerald Ferguson, GlaxoSmithKline

Stephen Ford, Military Vaccine Agency

Vicent Frascatore, Merck & Co., Inc.

Sylvina Frutos, GlaxoSmithKline

Mary Gadek, Novartis

Stanley A. Gall, American College of 

Obstetricians & Gynecologists

Diana Gaskins, Division of Public Health, 

Georgia Immunization Program

Richard Gesser, Merck Research Laboratories

Christopher Gilbert, Merck & Co., Inc.

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Ruth Gilmore, Georgia Immunization Program

Karen Goldenthal, Pharmanet Consulting

Michelle Goveia, Merck & Co., Inc.

John Gravenstein, Merck

Jesse Greene, SC Dept of Health and 

Environmental Control

Sylvester Gregg, Merck & Co., Inc.

Carolyn Griffing, Merck & Co., Inc.

Neal Halsey, Johns Hopkins University

Janice Hashimoto, Novartis

Richard Haupt, Merck & Co. Inc.

Alan Hinman, Task Force for Child Survival and 

Development

Phillip Hosbach, sanofi pasteur

Florence Houn, FDA

Wan-Ting Huang, CDC, Taiwan

Donnelle Humphrey-Franklin, Georgia DHR, 

Division of Public Health

Shirley Jankelevich, SC Dept of Health and 

Environmental Control

Uday Jodhpurkar, sanofi pasteur

David Johnson, sanofi pasteur

Eric Jones, sanofi pasteur

Nancy Kavanaugh, Medimmune, Inc.

Kevin Kelly, Merck Vaccine Division

Jason Kemner, GlaskoSmithKline

Glennie Kertes, Dwight D. Eisenhower Army 

Medical Center

David Kimberlin, AAP Committee on Infectious 

Diseases

Iftahar Koksal, Karadeniz Technical University, 

Turkey

Denise Kruzikas, GlaxoSmithKline

Barbara Kuter, Merck & Co., Inc.

Fred Lake, Cooney/Waters Group

Sarah Landry, GlaxoSmithKline

Scott Laster, Autism Parent

Jennifer Lastinger, Families Fighting Flu

Osman Leblibicioglu, Ondokuz Mayis 

University Medical School, Turkey

Grace Lee, Harvard Medical School

Marie-Michele Leger, American Academy of 

Physician Assistants

Jennifer Lichtner, Wyeth

Patrick Liedtka, Merck & Co., Inc.

Ding-Ping Liu, CDC, Taiwan

Brian Lotie, GlaxoSmithKline

Beverly Lybrand, Merck Vaccine Division

Andrew MacKnight, GlaxoSmithKline

Paul Madrazo, GlaxoSmithKline

Parthiv Mahadevia, Medimmune

Frank Malinoski, Medimmune

Leona Markson, Merck & Co., Inc.

Patrick Maroney, sanofi pasteur

Tara Martin, GlaxoSmithKline

Dean Mason, Wyeth

Marie Mazur, CSL Biotherapies

Jaime Micher, Asociacion Mexicana de 

Vacunologia

Patricia Montalvo, Las Vegas Palute Tribe 

Health and Human Services

Phillipe Monteyne, GlaxoSmithKline, Belgium

Kelly Moore, Tennessee Department of Health

Matthew Moore, CDC

Rebecca Morrison, SC DHEC Immunization 

Division

Jonathan Nelson, The Nelson Group

Timothy Obara, GlaxoSmithKline

Paul Offit, Children’s Hospital of Philadelphia

Kevin O’Neill, Wyeth Vaccines

Walter Orenstein, Emory University

Shefali Parikh, Merck & Co., Inc.

Joanne Pattenier, GlaxoSmithKline, Belgium

Tamer Pehlivan, sanofi pasteur, Turkey

Georges Peter, Brown Medical School

Diane Peterson, Immunization Action Coalition

Stanley Plotkin, sanofi pasteur

Gregory Poland, Mayo Clinic and Foundation

Isabel Quasha, European Association for CranioMaxiollo-Facial Surgery

Jane Quinn, GlaxoSmithKline

James Ransom, NACCHO

Mobeen Rathore, University of Florida

Jill Ray, Georgia Chapter – AAP

Greg Reed, CDC/NCIRD

Margaret Rennels, GlaxoSmithKline

Christina Richards, Johns Hopkins University 

Student Health Center

Lauren Riley, Infectious Diseases in Children, 

Slack Inc.

Julian Ritchey, sanofi pasteur

Maria Angela Roa, SciMed

Matthew Rousculp, Medimmune

Fred Ruben, sanofi pasteur

Alfred Saah, Merck & Co., Inc.

Thomas Saari, AAP Immunization Task Force

Patricia Sadler, Merck Research Laboratories

David Schechter, Merck & Co., Inc.

Laurie Schowalter, GlaxoSmithKline

Jason Schwartz, University of Pennsylvania

Anne Elizabeth Schuind, GlaxoSmithKline

Rosanna Selse, Johns Hopkins University

Tej Sha, WellCare

Tom Shin, Baxter BioSciences

Judith Shindman, sanofi pasteur, Canada

Jennifer Shu, Children’s Medical Group, P.C.

Alan Sievert, American Academy of Pediatrics, 

GA Chapter

Heidi Spelete, Pediatric News

Silvija Staprans, Merck Vaccine Division

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Gary Stein, Families Fighting Flu

Kurt Stembridge, GlaxoSmithKline

Mike Stobbe, Associated Press

Raymond Strikas, National Vaccine Program 

Office, HHS

Stacy Stuerke, Merck Vaccine Division

Florence Synn, Merck & Co., Inc.

Lonnie Thomas, Henry Schein Inc.

Rosemary Tierman, FDA/Division of Vaccines

John Trizzino, Medimmune

Theodore Tsai, Novartis

Mariam E. Tucker, Pediatric News

James Tursi, GlaxoSmithKline

Anastasios Tsirpouchtsidis, GlaxoSmithKline

Nevzat Ata Ualcin, Akdeniz University, Turkey

Sercan Ulusoy, Ege University, Turkey

Gaye Usluer, Eskisehir Osmangazi University, 

Turkey

Thomas Vernon

Peter Vigliarolo, Cooney/Waters

Michael Vinluan. CDC-INFO/Constella Group

Steven Vitale, GlaxoSmithKline

Robert Walker, Medimmune, Inc.

Joel Ward, Novartis

James Wassil, Merck & Co., Inc.

Barbara Watson, Philadelphia Department of 

Public Health

Rita Watson, Epilepsy Therapy Development 

Project

Deborah Wexler, Immunization Action Coalition

Patricia Whitley-Williams, UMDNJ Robert 

Wood Johnson Medical School

Matt Whitmann, GlaxoSmithKline

Mark Willmann, McCann Healthcare

Marcellette Wise, Wyeth Pharmaceuticals

Eileen Yamanda, California Department of 

Health Services

Laura Jean York, Wyeth Vaccines

Jennifer Zavolinsky, Every Child by Two

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Attachment Two: Acronyms

AAP American Academy of Pediatrics

ACIP Advisory Committee on Immunization Practices 

CDC Centers for Disease Control and Prevention 

CMS Centers for Medicare and Medicaid Services

DHHS Department of Health and Human Services 

FDA Food and Drug Administration 

HCUP Healthcare Utilization Project 

HRSA Health Resources and Services Administration 

IOM Institute of Medicine 

ISO Immunization Safety Office

NCHHSTP National Center for HIV, Hepatitis, STD and TB Prevention 

NCIRD National Center for Immunization and Respiratory Diseases 

NIH National Institutes of Health

NVAC National Vaccine Advisory Committee

NVPO National Vaccine Program Office

NVSN New Vaccine Surveillance Network

VAERS Vaccine Adverse Event Reporting System 

VFC Vaccines for Children

VSD Vaccine Safety Datalink

This document has been archived for historical purposes.